JPH0789868A - Preventive and/or therapeutic agent for hypofunction of organ caused by operation or transplant of organ - Google Patents

Abstract

PURPOSE:To obtain a preventive and therapeutic agent for hypofunction of an organ caused by operation or transplant of the organ, containing a compound having an endoserine receptor antagonism. CONSTITUTION:A cyclic peptide of the formula (X and Y are each an alpha-amino acid residue; A is a D-acidic-alpha-amino acid residue; B is a neutral alpha-amino acid residue; C is an L-alpha-amino acid residue; D is a D-alpha-amino acid residue containing an aromatic ring) or its salt is contained as the active component. As the compound of the formula, cyclo{D-aspartic acid-N<4>-[20(indol-3-yl)ethyl-asparagine- aspartic acid-D-leucine-leucine-D-tryptophan} is exemplified. This medicine is useful for therapy and prevention of hypofunction of an organ such as the liver, the kidney, the heart, the lien or the pancreas, especially the liver. In the case of parenteral administration, e.g. injection, the dosage is 0.01 to 100mg/kg per one operation. In the case of oral administration, it is 5mg to 1g/kg.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a preventive and / or therapeutic agent for functional decline of organs which occurs during surgery or transplantation of organs containing a compound having an endothelin receptor antagonistic action.

[0002]

2. Description of the Related Art Endothelin (ET) was introduced in 1988,
A vasoconstrictive peptide consisting of 21 amino acids that was isolated from the culture supernatant of porcine aortic endothelial cells by Yanagisawa et al. And its structure was determined [Yanagisawa et al., Nature, 33.
2, pp. 411-412]. Then, the study of the gene encoding endothelin revealed that there are peptides with a structure similar to endothelin, and endothelin-1 (ET-1) and endothelin-2 (E
T-2) and endothelin-3 (ET-3). In addition, there are A-type and B-type receptors for endothelin.
It is revealed that the type exists. Since the discovery of endothelin, with the aim of developing a therapeutic agent for diseases caused by endothelin, a search for a compound having an endothelin receptor antagonistic activity has been carried out vigorously, and as a result, a compound having an endothelin receptor antagonistic activity has been identified. Japanese Patent Application No. 4-344252 (EP-A-552,48
9), Japanese Patent Application No. 4-216019 (EP-A-528,3)
12), Japanese Patent Application No. 4-27785 (EP-A-499,2)
66), Japanese Patent Application No. 3-503831 (WO91 / 1308).
9), EP-A-436,189, EP-A-457,1
95, EP-A-510,526, WO92 / 1299.
1, JP-A-4-288099, EP-A-496,45
2, EP-A-526,708, EP-A-460,6
79, WO92 / 20706, etc. have been proposed. It is suggested that the compounds described therein are effective as a therapeutic agent for hypertension, a therapeutic agent for cardio-cerebral circulation disease, a therapeutic agent for renal disease, a therapeutic agent for asthma, an anti-inflammatory agent, an anti-arthritic agent and the like. On the other hand, it is known that endothelin concentration in organs increases during surgery of organs such as the liver (Journal of the Japan Society of Transplantation, VOL.27, 1992), and recently, monoclonal antibodies against endothelin have a function of preventing functional decline of surgical organs. It was revealed to have. However, there is no description or suggestion that a compound having an endothelin receptor antagonism is useful as a preventive or therapeutic agent for organ function deterioration occurring during organ surgery or transplantation.

[0003]

DISCLOSURE OF THE INVENTION The present invention comprises a compound containing an endothelin receptor antagonistic activity, which prevents the functional deterioration of organs caused by surgery or transplantation of organs and / or
Alternatively, it is intended to provide a therapeutic agent.

[0004]

[Means for Solving the Problems] As a result of intensive studies to solve the above problems, the present inventors have hitherto found a therapeutic agent for hypertension, a therapeutic agent for cardiac / cerebral circulatory disease, a therapeutic agent for renal disease, a therapeutic agent for asthma, A compound having an endothelin receptor antagonistic action, which has been considered to be effective as an anti-inflammatory agent or an anti-arthritic agent, is unexpectedly used as a preventive and / or therapeutic agent for organ function deterioration that occurs during surgery or transplantation of an organ, especially The present invention was found to be effective as a preventive and / or therapeutic agent for lowering liver function, and as a result of further studies, the present invention has been completed. That is, the present invention is a preventive and / or therapeutic agent for functional decline of organs which occurs during surgery or transplantation of organs, which comprises a compound having an endothelin receptor antagonistic action. In the present invention, when abbreviated symbols such as amino acids and peptides are used, they are IUP.
AC-IUB Commission on Biochemical Nomenclatur
It is based on the abbreviations based on e or the abbreviations commonly used in this field, examples of which are given below. When optical isomers exist, they represent the L isomer unless otherwise specified. Ala: Alanine Arg: Arginine Asn: Asparagine acid Asp: Aspartic acid Cys: Cysteine Glu: Glutamic acid Gln: Glutamine Gly: Glycine His: Histidine Ile: Isoleucine Leu: Leucine Lys: Lysine Met: Methionine Phe: Phenylalanine Pro: Proline Ser: Serine Thr : Threonine Trp: tryptophan Tyr: tyrosine Val: valine Abu: 2-aminobutyric acid α-Aba: L-α-aminobutanoic acid Ac3c: 1-aminocyclopropanecarboxylic acid Ac4c: 1-aminocyclobutanecarboxylic acid Ac5c: 1-amino Cyclopentanecarboxylic acid Ac6c: 1-aminocyclohexanecarboxylic acid Ac7c: 1-aminocycloheptacarboxylic acid Acpr: 1-Amino cyclopropane -1
-Carboxylic acid Acbu: 1-aminocyclobutane-1-
Carboxylic acid Acpe: 1-aminocyclopentane-1
-Carboxylic acid Achx: 1-aminocyclohexane-1
-Carboxylic acid Achp: 1-aminocycloheptane-1
-Carboxylic acid εAhx: ε-aminocaproic acid Aib: 2-aminoisobutyric acid aIle: L-alloisoleucine βAla: β-alanine Alg: 2-amino-4-pentenoic acid (allylglycine) Arg (NO ₂ ): ^NG -nitro. arginine Arg (Tos): N ^G -p- toluenesulfonyl arginine _{Asn (CH 2 Ph): N} 4 - benzyl aspartate _{Asn (CH 2 CH 2 Ph)} : N 4 - phenethyl asparagine _{Asn (CH 2 CH 2 -Ind)} : N ⁴ - (2- {indol-3-yl} ethyl) asparagine _{Asn (Me · CH 2 CH 2} Ph): N 4 - methyl -N ⁴ - phenethyl asparagine _{Asn (CH 2 CHMePh): N} 4 - ({2 -Phenyl} propyl) asparagine Asp (R1): aspartic acid β-4-phenylpiperazine amide Asp (R2): aspartic acid β-4-f Nylpiperidine amide Asp (R3): Aspartic acid β-indoline amide Asp (R4): Aspartic acid β-1-aminoindan amide Asp (R5): Aspartic acid β-1-aminotetrahydronaphthaleneamide Asp (R6): Aspartic acid β-4-acetylpiperazine amide Atm: 2-amino-3- (2-amino-5-thiazole) propanoic acid Azc: azetidine-2-carboxylic acid Bip: (P-phenyl) phenylalanine Cta: cysteic acid Cpg: cyclopentylglycine Cpn: 2-amino-3-cyclopropanepropanoic acid (cyclopropylalanine) Cha: cyclohexylalanine Chx: cyclohexylalanine (hexahydroxyphenylalanine) C3al: L-3-cyclopropylalanine C4al: L-3-cycl Butylalanine C5al: L-3- cyclopentyl-alanine C6al: L-3- cyclohexylalanine CmGly: N- (carboxymethyl) glycine CpGly: N- cyclopentyl glycine Cys (O ₃ H): L- cysteic acid Cys (O ₃ Na) : sodium L- cysteic acid DCpg: D-2- cyclopentyl glycine DCHG: D-2-cyclohexylglycine DCys (O ₃ H): D- cysteic acid DCys (O ₃ Na): sodium D- cysteic acid DCys (O ₃ Bu ₄ N): tert-butylammonium D-cysteic acid DDpg: D-2- (1,4-cyclohexadienyl) glycine DEtg: (2S) -2-ethyl-2-
(2-thienyl) glycine DFug: D-2- (2-furyl) glycine DGlu: D-glutamic acid DαAba: D-α-aminobutanoic acid DAla: D-alanine DAsp: D-aspartic acid DAsp (ONa): D-asparagine. Sodium acid salt DBta: D-3- (3-benzo [b] thienyl) alanine DPen: D-penicylamine DTha: D-3- (2-thienyl) alanine DThg: D-2- (2-thienyl) glucine DThr: D -Threonine DIle: D-isoleucine Dale: D-alloisoleucine DItg: D-2- (isothiazole) glycine DLeu: D-leucine DtertLeu: D-2-amino-3,3-dimethylbutanoic acid DTrp: D-tryptophan DTrp. (CHO): N in-formyl-D-tryptophan DTrp (O): D-3- (2,3-dihydro-
2-oxoindol-3-yl) alanine DTrp ((CH ₂ ) mCOR ₁ ): at the 1-position of the indole ring-
D-tryptophan DTyr: D-tyrosine DNal: D-3- (1-naphthyl) alanine DNva: D-norvaline DTza: D-3- (2-thiazole) alanine DTzg: substituted with a (CH ₂ ) mCOR ₁ group. D-2- (thiazolyl) glycine DVal: D-valine Dip: 3,3-diphenylalanine DNle: D-norleucine DPhe: D-phenylalanine DPhg: D-phenylglycine Emg: 2-amino-4,5 (RS)-
Epoxy-4-pentenoic acid GABA: γ-aminobutyric acid Gln (CH ₂ Ph): N ⁵ -benzylglutamine Gln (CH ₂ CH ₂ Ph): N ⁵ -phenethylglutamine Gln (CH ₂ CH ₂ -Ind): N ⁵ -(2- {Indole-3-
Ill} ethyl) glutamine Glu (R3): glutamic acid γ-indoline amide Glu (R4): glutamic acid γ-1-aminoindanamide Glu (R5): glutamic acid γ-1-aminotetrahydronaphthalenamide His (Bom): N (π ) - benzyloxymethyl histidine His (Bzl): N (τ ) - benzyl histidine 3Hyp: 3- hydroxyproline Hyp: 4-hydroxyproline His (Dnp): N ^im -2,4- dinitrophenyl histidine homoPhe: 2-amino -5-Phenylpentanoic acid Hyp (Bzl): 4-benzyloxyproline iPrGly: N-isopropylglycine IeGly: N- [2- (4-imidazole) ethyl] glycine (I) Tyr: 3-iodotyrosine Lys (CHO). : N ⁶ - formyl -L- lysine Lys (Mtr): N (ε ) - (4- methoxy - Two,
3,6-Trimethylbenzenesulfonyl) lysine tLeu: tertiary leucine γMeLeu: gamma methylleucine MeAla: N-methyl-L-alanine MeLeu: N-methyl-L-leucine MeMet: N-methyl-L-methionine Met (O). : methionine sulfoxide Met (O _2): methionine sulfone Mpr: 3- mercaptopropionic acid Nva: norvaline Nle: norleucine Nal (1): 3- (1- naphthyl) alanine Nal (2): 3- (2- naphthyl) alanine N-MePhe: N-methylphenylalanine N-MeAsp: N-methylaspartic acid 1-Nal: 3- (1'-naphthyl) alanine 2-Nal: 3- (2'-naphthyl) alanine Nia: 2-amino-3. -Cyanopropanoic acid (cyanoalanine) N-MeLe : N- methyl-leucine N-MeTrp: N (α) - methyl tryptophan Orn: ornithine Orn (CHO): N ⁵ - formyl -L- ornithine Orn (COPh): N (δ ) - benzoyl Ornithine Orn (COCH ₂ Ph) : N (δ) -phenylacetylornithine Orn (COCH ₂ CH ₂ Ph): N (δ)-(3-phenylpropionyl) ornithine Orn (COCH ₂ -Ind): N (δ)-({indol-3-yl } Acetyl) ornithine Phe (4F): 4-fluorophenylalanine Phg: Phenylglycine Pip: Pipecolic acid (piperidine-2
-Carboxylic acid) Pgl: phenylglycine Pgy: 2-aminopentanoic acid (propylglycine) Pha: 2-amino-6- (1-pyrrole) -hexanoic acid Pyr: 2-amino-3- (3-pyridyl) -propane Acid (3-pyridylalanine) (p-F) Phe: Parafluorophenylalanine Pya (2): 2-Pyridylalanine Pya (3): 3-Pyridylalanine Sar: Sarcosine (N-methylglycine) Ser (Bzl): O - benzyl serine (m-F) Tyr: meta-fluoro-tyrosine Trp (Me): N ⁱⁿ - methyl tryptophan _{Trp (CH 2 OH): N} in - hydroxymethyl tryptophan Trp (CHO): N ⁱⁿ - formyl tryptophan mTrp: 5- methyl-tryptophan Trp (For): N ⁱⁿ - ho Mill tryptophan Trp (Ac): N ⁱⁿ - acetyl tryptophan (I) Tyr: 3- iodotyrosine Tyr (Et): O- ethyl - tyrosine Tyr (OEt): O- ethyl - Tyrosine Tyr (Ot-Bu): O- tert-Butyl-tyrosine Tyr (OMe): O-methyl-tyrosine Thg (2): 2- (2-thienyl) glycine Thg (3): 2- (3-thienyl) glycine Thi: 3- (2-thienyl) Alanine tLeu: t-leucine Thr (Bzl): O-benzyl threonine Tpr: thioproline Tic: 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid Tza: 2-amino-3- (4-thiazolyl) -propane acid Tza: L-3- (2- thiazole) alanine Trp (For): N ⁱⁿ - Horumirutori Ptophan Tha: L-3- (2-thienyl) alanine Thz: L-thiazolidine-4-carboxylic acid Further, the substituents, protecting groups and reagents are represented by the following symbols. AcOEt: ethyl acetate Ac: acetyl Ada: 1-adamantyl acetic acid Adoc: adamantyloxycarbonyl Boc: tert-butoxycarbonyl Bzl: benzyl Boc: tert-butoxycarbonyl Bom: benzyloxymethyl 2-Br-Z: O-bromobenzyloxycarbonyl. 2-ClZ: O-chlorobenzyloxycarbonyl ClZ: 2-chlorobenzyloxycarbonyl CH ₃ CN: acetonitrile DMAP: 4-dimethylaminopyridine DMF: dimethylformamide DCC: N, N'-dicyclohexylcarbodiimide DCU: N, N '-Dicyclohexylurea DCM: dichloromethane DIEA: N, N-diisopropylethylamine DCHA: N, N'-dicyclohexylamine Dba: 1 , 11-dihydro -5H-
Dibenz (b, f) azepin-5-yl DIPC: N, N'-diisopropylcarbodiimide DMSO: dimethylsulfoxide Dnp: 2,4-dinitrophenyl EDT: 1,2-ethanedithiol EDCl.HCl: 1-ethyl-3- (3-Dimethylaminopropyl) carbodiimide hydrochloride For: Formyl Fmoc: 9-fluorenylmethyloxycarbonyl HONB: N-hydroxy-5-norbornene-2,3-dicarboximide HOBt: N-hydroxybeztriazole HOBt: 1 - hydroxybenzotriazole HOAc: acetic acid HCl: hydrochloric acid HF: hydrogen fluoride HOBT · H ₂ O: 1- hydroxy -1H- benzotriazole 1 hydrated HEPES: 2- [4- (2- hydroxyethyl) -1-piperazinyl ] Ethanesulfonic acid IBCF: Isobutylchloroformate Ind: 1-carboxyindane-2-
Ilk: 3-carboxy-1,2,3
4- tetrahydroisoquinolin-2-yl KOH: potassium hydroxide MOPS: 3- Morpholinopropanesulfonic acid MBHA Resin: p-methylbenzhydrylamine resin MeBzl: 4-methylbenzyl NO _2: nitro OPac: Phenacyl ester OBzl: benzyl ester ONB: HONB ester Pym: Pyrimidyl Pip: Piperazyl Pac: Phenacyl Pfp: Pentafluorophenyl p-TosOH: p-Toluenesulfonic acid Pd / C: Palladium-carbon PMSF: Phenylmethanesulfonyl fluoride Ph: Phenyl PAM Resin: 4- ( (Oxymethyl) -phenylacetamide methyl resin Tos: paratoluenesulfonyl TosOH: paratoluenesulfonic acid TFA: trifluoro Acetate TEA: Triethylamine THF: Tetrahydrofuran tBu: tert-Butyl TBS: tert-Butyldimethylsilyl Tos: 4-Toluenesulfonyl (tosyl) Trt: Triphenylmethyl (trityl) Tris: Tris (hydroxymethyl) aminomethane WSCD: 1-Ethyl -3- (3-dimethylaminopropyl) carbodiimide Z: benzyloxycarbonyl

[0005]

[Chemical 2]

[0006] The present invention is (1) a preventive and / or therapeutic agent for organ function deterioration occurring during surgery or transplantation of an organ, which comprises a compound having an endothelin receptor antagonistic action,
More preferable modes include the following (2) to (35). (2) The preventive and / or therapeutic agent according to (1), wherein the organ is the liver, (3) a compound having an endothelin receptor antagonistic action,
Formula [A]

[0007]

[Chemical 3]

[Wherein X and Y are α-amino acid residues, A is a D-acidic-α-amino acid residue, and B is a neutral-amino acid residue.
α-amino acid residue, C represents L-α-amino acid residue, D represents D-α-amino acid residue having an aromatic ring group] or a cyclic peptide thereof, or a salt thereof, (1) The preventive and / or therapeutic agent according to (4) the cyclic peptide or salt thereof, wherein A is C _3-5 -D-acidic-α-amino acid residue, preferably C
_A compound which is a _3-5 -D-α-aminodicarboxylic acid residue, a C _3-11 -L-α-amino acid residue in which X may be substituted, preferably a heterocyclic group which may have a substituent A compound which is a C _3-5 -L-α-aminodicarboxylic acid residue which may be substituted with a ring group, Y is an L-acidic α-amino acid residue, preferably C _3-5 -L-α-
A compound which is an aminodicarboxylic acid residue, B may be substituted with a C _2-6 -D-neutral-α-amino acid residue which may have a heterocyclic group, preferably a sulfur-containing heterocyclic group A compound which is a good C _2-6 -D-α-aminomonocarboxylic acid residue, C is an L-neutral-α-amino acid residue, preferably C _5-6 -L-α
-A compound that is an aminomonocarboxylic acid residue, or a D-neutral-α-amino acid residue having an aromatic heterocyclic group in which D is optionally acylated, preferably a nitrogen-containing aromatic heterocyclic group (3) The preventive and / or therapeutic agent according to (3), which is a compound having a D-neutral-α-amino acid residue, (5) the cyclic peptide or a salt thereof is Cyclo [-D-Asp-Asn
(CH ₂ CH ₂ -Ind) -Asp-D-Leu-Leu-D-Trp-], Cyclo 〔-D-Asp
-Trp-Asp-D-Leu-Leu-D-Trp (For)-], Cyclo 〔-D-Asp-Tr
p-Asp-D-Thg (3) -Leu-D-Trp-], Cyclo 〔-D-Asp-Trp-Asp
-D-γMeLeu-Leu-D-Trp-], Cyclo 〔-D-Asp-Trp-Asp-DT
hg (2) -Leu-D-Trp-], Cyclo 〔-D-Asp-Gln (CH ₂ Ph) -Asp-D
-Leu-Leu-D-Trp-], Cyclo 〔-D-Asp-Asp (R1) -Asp-D-Leu
-Leu-D-Trp-], Cyclo 〔-D-Asp-Asp (R2) -Asp-D-Leu-Leu
-D-Trp-], Cyclo 〔-D-Asp-Orn (COCH ₂ Ph) -Asp-D-Leu-Le
uD-Trp-], Cyclo 〔-D-Asp-Orn (COCH ₂ -Ind) -Asp-D-Leu
-Leu-D-Trp-], Cyclo 〔-D-Asp-Hyp (Bzl) -Asp-D-Thg (2)
-Leu-D-Trp-], Cyclo 〔-D-Asp-Gln (Bzl) -Asp-D-Thg (2)
-Leu-D-Trp-], Cyclo 〔-D-Asp-Asn (CH ₂ CH ₂ -Ind) -Asp-D
-Thg (2) -Leu-D-Trp-], Cyclo 〔-D-Asp-Asp (R1) -Asp-D-
Thg (2) -Leu-D-Trp-], Cyclo 〔-D-Asp-Asp (R7) -Asp-DT
hg (2) -Leu-D-Trp-], Cyclo 〔-D-Asp-Asp (R10) -Asp-DT
hg (2) -Leu-D-Trp-], Cyclo 〔-D-Asp-Asp (R12) -Asp-DT
hg (2) -Leu-D-Trp-], Cyclo 〔-D-Asp-Asp (R13) -Asp-DT
hg (2) -Leu-D-Trp-], Cyclo 〔-D-Cta-Asp (R1) -Asp-D-Th
g (2) -Leu-D-Trp-], Cyclo 〔-D-Cta-Asp (R7) -Asp-D-Thg
(2) -Leu-D-Trp-], Cyclo 〔-D-Cta-Asp (R10) -Asp-D-Thg
(2) -Leu-D-Trp-], Cyclo 〔-D-Cta-Asp (R12) -Asp-D-Thg
(2) -Leu-D-Trp-], Cyclo 〔-D-Cta-Asp (R13) -Asp-D-Thg
(2) -Leu-D-Trp-], Cyclo 〔-D-Asp-Asp (R1) -Asp-D-Cpg-
Leu-D-Trp-], or Cyclo 〔-D-Cta-Asp (R1) -Asp-D-Cp
g-Leu-D-Trp-], (3) the preventive and / or therapeutic agent according to (6) a compound having an endothelin receptor antagonistic action,
Formula [B]

[0009]

[Chemical 4]

[In the formula, R ₁ is a lipophilic group, R ₂ and R ₅ are each a hydrogen atom or a lower alkyl group, and R ₃ is an aliphatic group which may contain an oxygen atom or a sulfur atom, R ₄ is an optionally substituted heterocycle-lower alkyl group, R ₆ is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted aromatic ring group, and X is an aromatic ring. Group, n is 0 or an integer of 1 or more, and m is an integer of 2 or more. ] It is a peptide or its salt represented by,
(1) The preventive and / or therapeutic agent according to (7), the peptide or its salt is Hexamethyleneimino-C.
O-Leu- (D) Trp- (D) Ala-βAla-Tyr- (D) Phe-OH or salt thereof, Hexamethyleneimino-CO-Leu- (D) Trp- (D) Ala-βAl
a-Tyr (I)-(D) Phe-OH or its salt, or Hexamethyl
eneimino-CO-Leu- (D) Trp- (D) Ala-βAla-Trp-NH-Ind-OH
(6) The preventive and / or therapeutic agent according to (6), (8) the compound having an endothelin receptor antagonistic action,
Formula [C]

[0011]

[Chemical 5]

[In the formula, M represents a mercaptoacyl group,
P, Q, R, S, T, U, V, W, X, Y and Z each represent an amino acid residue, which may be L-, D- or DL-form, and the amino acid side chain of Y Is a substituted saturated aliphatic hydrocarbon group having 1 to 15 carbon atoms or an unsubstituted saturated aliphatic hydrocarbon group having 4 to 15 carbon atoms other than (1S) -1-methylpropyl group]
(1) The preventive and / or therapeutic agent according to (1), which is a peptide represented by or a pharmacologically acceptable salt thereof, (9) a compound having an endothelin receptor antagonism, 1 CysSerCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviation: [Thr18, Leu, Leu ] ET-1: SEQ ID NO: 1) 2 CysSerCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuThrChaIleTrp (abbreviated [Thr18, Cha19] ET-1: SEQ ID NO: 2) 3 CysSerCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuThrPheIleTrp (abbreviated [Thr18, Phe19] ET-1: SEQ ID NO: 3) 4 CysSerCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuThrγLeuIleTrp (abbreviated [Thr18, γLeu19] ET-1: SEQ ID NO: 4) 5 CysSerCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuThrAsnIleTrp (abbreviated [Thr18, Asn19] ET-1: SEQ ID NO: 5) 6 CysSerCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuSerLeuIleTrp (abbreviated [Ser18, Leu19] ET-1: SEQ ID NO: 6) 7 CysSerCysSerSerLeuMetAspLysGluCysVal TiwairPheCysHisLeuAsnLeuIleTrp (abbreviated [Asn18, Leu19] ET-1: SEQ ID NO: 7) 8 CysSerCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuGlyLeuIleTrp (abbreviated [Gly18, Leu19] ET-1: SEQ ID NO: 8) 9 CysThrCysPheThrTyrLysAspLysGluCysValTyrTyrCysHisLeuThrLeuIleTrp (abbreviated [Thr18, Leu19] ET-3: SEQ ID NO: 9) 10 CysSerCysSerSerLeuMetAspAlaGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviated [Ala9, Thr18, Leu19] ET-1: SEQ ID NO: 10) 11 MprSerCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviated [Mpr1, Thr18, Leu19] ET-1: SEQ ID NO: 11) 12 CysAlaCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviated [Ala2, Thr18, Leu19] ET -1: SEQ ID NO: 12) 13 CysSerCysAlaSerLeuMetAspLysGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviated [Ala4, Thr18, Leu19] ET-1: SEQ ID NO: 13) 14 CysSerCysSerAlaLeuMetAspLysGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviated [Ala5, Thr18, Leu19] ET-1: SEQ ID NO: 14) 15 CysSerCysSerSerAlaMet EiesupieruwaiesujieruyushiwaiesubuieierutiwairPheCysHisLeuThrLeuIleTrp (abbreviated [Ala6, Thr18, Leu19] ET-1: SEQ ID NO: 15) 16 CysSerCysSerSerLeuAlaAspLysGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviated [Ala7, Thr18, Leu19] ET-1: SEQ ID NO: 16) 17 CysSerCysSerSerLeuNleAspLysGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviated [Nle7, Thr18, Leu19] ET- 1: SEQ ID NO: 17) 18 CysSerCysSerSerTrpLeuAspLysGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviation: [Thr18, Leu19] ET-2: SEQ ID NO: 18), (10) A compound having antagonistic action against a compound having an endothelin receptor according to (8) , General formula [D]

[0013]

[Chemical 6]

[Wherein A, B, C, D, E and F are L
An amino acid residue, (i) A = Ser, C = Ser, D
= Leu, E = Met and F = Phe, (ii) A = Ser, B = Se
r, C = Ser, D = Trp, E = Leu and F = Phe, or (iii) A = Thr, B = Phe, C = Thr, D = Tyr, E = Lys
And F is any of Tyr, W, X, Y and Z are amino acid residues (which may be D-, L- or DL-forms), and at least one of W and Y is L-.
It is an amino acid residue other than an alanine residue or an L-cysteine residue, X is an amino acid residue other than an L-lysine residue, or Z is an amino acid residue other than an L-aspartic acid residue. It is represented by
(1) prevention and / or therapeutic agent according, (11) a compound having endothelin receptor antagonistic activity, wherein [E] ^{Cyclo (-X 1 -X 2 -X 3} -X 4 -
X ⁵⁾ [E] (wherein, Xn (n represents an integer of 1 to 5) .X ¹ showing the amino acid D-Phe, D-Tyr, D-Tha, D-Tz
a, D-Nal, D-Bta, D-Trp, D-Trp (O), D-Trp
(CHO) or D-Trp [(CH ₂ ) mCOR ¹ ], wherein m is 0 to 6
R ¹ represents a hydroxyl group, a C _1-6 alkoxy group, an amino group or a C _1-6 monoalkylamino group. X ² is D-As
p, D-Glu or D-Cys (O ₃ H) is shown. X ³ is Pro, Hyp, P
ip, Thz, β-Ala or Gly, Ala, α-Aba, Aib, Val, N
va, Leu, Ile, alle, Nle, Met, Met (O), Met (O ₂ ), Ph
e, Tza, Tha, Tyr, Trp, His, Arg, Lys, Lys (CHO), Or
n, Orn (CHO), Asn, Gln, Asp, Glu, Cys (O ₃ H), Cys, Se
r or Thr, the hydrogen atom on the α-amino group may have a group selected from the group consisting of an imidazolyl group, a carboxyl group, a sulfo group and a hydroxyl group.
_It may be substituted with a _1-6 alkyl or a C _3-7 cycloalkyl group. X ⁴ is D-Ala, D-Thr, D-αAba, D-Va
l, D-Nva, D-Leu, D-Ile, D-alle, D-Nle,
D-tertLeu, D-Cpg, D-Chg, D-Dpg, D-Pen, A
ib, Ac3c, Ac4c, Ac5c, Ac6c, Ac7c (Aib to Ac7c are L
-, D- and DL- may be used), or D-
Phg, D-Thg, D-Fug, D-Tzg or D-Itg is shown,
The hydrogen atom on the α-amino group may be substituted with a C _1-3 alkyl group. X ⁵ is Pro, Pip, Thz, or His, Ala, α
Aba, Val, Nva, Leu, Ile, alle, Nle, Met, C3al, C4a
l, C5al or C6al is shown, and the hydrogen atom on the α-amino group may be substituted with a C _1-6 alkyl group. ] The preventive and / or therapeutic agent according to (1), which is a cyclic pentapeptide represented by the formula (4) or a pharmaceutically acceptable salt thereof, (12) The cyclic pentapeptide is Cyclo (-D-Asp-Pro-D-Val
-Leu-D-Trp-), Cyclo (-D-Cys (0 ₃ H) -Pro-D-Val-Leu-D-Tr
p-), Cyclo (-D-Asp-Pro-D-Thg (2) -Leu-D-Trp-) or Cy
clo (-D-Asp-Pro-D-Cpg-Leu-D-Trp-), the preventive and / or therapeutic agent according to (11), (13) the compound having an endothelin receptor antagonistic activity is represented by the formula [F ]

[0015]

[Chemical 7]

(In the formula, R ¹ represents a hydrogen atom or an acyl group. R ² represents a lower alkyl group, an optionally substituted ar (lower) alkyl group, cyclo (lower) alkyl (lower))
It represents an alkyl group or an optionally substituted heterocyclic (lower) alkyl group. R ³ represents an optionally substituted heterocyclic (lower) alkyl group or an optionally substituted ar (lower) alkyl group. R ⁴ represents a hydrogen atom or an optionally substituted lower alkyl group. R ⁵ represents a carboxyl group, a protected carboxyl group, a carboxy (lower) alkyl group or a protected carboxy (lower) alkyl group. R ⁶ represents a hydrogen atom or an optionally substituted lower alkyl group. R ⁷ represents a hydrogen atom or a lower alkyl group. A represents -O-, -NH-, a lower alkylamino group or a lower alkylene group. However, R ² is (S)-
An isobutyl group, R ³ is an N- (dichlorobenzyloxycarbonyl) indol-3-ylmethylene group, and R ⁴
Is a methyl group, R ⁵ is a methoxycarbonyl group, R ⁶ is a hydrogen atom, R ⁷ is a hydrogen atom and A is —NH—.

[0017]

[Chemical 8]

Has an absolute configuration of The preventive and / or therapeutic agent according to (1) 1, which is a peptide represented by the formula (4) or a pharmaceutically acceptable salt thereof.

(14) A compound having an endothelin receptor antagonistic activity is represented by the formula [G]

[0020]

[Chemical 9]

(In the formula, R ¹ represents a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halogen atom or a trifluoromethyl group. R ² represents a halogen atom, a lower alkoxy group, a hydroxy lower alkoxy group or trifluoromethyl group. R ³ represents a hydroxy group, a halogen atom, an alkylthio group, a cycloalkyl group, a hydroxy lower alkyl group, a hydroxy lower alkoxy group, a hydroxyimino lower alkyl group, a lower alkenyl group, an oquino lower alkyl group, a trifluoromethyl group, A trifluoromethoxy group, a lower alkoxy group, a lower alkoxy lower alkoxy group or an aryl lower alkoxy group may be shown, and R ² and R ³ may form butadienyl, wherein R ⁴ is a lower alkyl group, an aryl group or a heteroaryl group. shown .R ⁵ is lower alkanoyl group, Shows the Nzoiru group, heterocyclic carbonyl group or a tetrahydropyran-2-yl group .R ⁶ is formula

[0022]

[Chemical 10]

Is shown. R ⁷ represents a lower alkoxy group or a nitro group. R ⁸ represents a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a nitro group, a hydroxy group, an amino group or a trifluoromethyl group,
R ⁷ and R ⁸ may form butadienyl. R ⁹ represents a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group or a trifluoromethyl group. R ¹⁰ represents a halogen atom, a lower alkyl group, a lower alkoxy group or a lower alkylthio group. X and Y each represent O, S or NH. n is 2, 3 or 4. And a compound represented by the formula (1) or a salt thereof,
Or a therapeutic agent.

(15) A compound having an endothelin receptor antagonistic action is represented by the formula [H]

[0025]

[Chemical 11]

Wherein R ¹ is hydrogen or a metabolizable ester residue, R ³ is an optionally substituted aryl or an optionally substituted aromatic heterocycle, and one of X and Y is hydroxy. The other is a trityl pen derivative represented by hydrogen, or X and Y together represent oxo, and Z represents oxygen or two hydrogens.) The preventive and / or therapeutic agent according to claim 1, (16) A compound having an endothelin receptor antagonistic activity is represented by the formula [I]

[0027]

[Chemical 12]

Where Xaa1 represents Tyr, Phe or Ala, Xaa2 represents Asp or Gly, and Xaa3 represents Trp.
Or Phe. The prophylactic and / or therapeutic agent according to (1), which is an endothelin derivative represented by the formula (17):

[0029]

[Chemical 13]

The preventive and / or therapeutic agent according to claim 1, which is a cyclic peptide represented by the formula (18):

[0031]

[Chemical 14]

(In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halogen atom or a trifluoromethyl group. R ² represents a hydrogen atom, a halogen atom, a lower alkoxy group, a trifluoro group. A methyl group or —OCH ₂ COOR ^a , R ³ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkylthio group, a trifluoromethyl group, a cycloalkyl group, a lower alkoxy group or a trifluoromethyl group, and R ² And R ³
May form butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy. R ⁴
Is a hydrogen atom, lower alkyl group, cycloalkyl group, trifluoromethyl group, lower alkoxy group, lower alkylthio group, lower alkylthio lower alkyl group, hydroxy lower alkyl group, hydroxy lower alkoxy group, lower alkoxy lower alkyl group, hydroxy lower alkoxy Lower alkyl group, hydroxy lower alkoxy lower alkoxy group, lower alkylsulfinyl group, lower alkylsulfonyl group, 2-methoxy-3-hydroxypropoxy group,
2-hydroxy-3-phenylpropyl group, amino lower alkyl group, lower alkylamino lower alkyl group, dilower alkylamino lower alkylamino group, lower alkylamino group, dilower alkylamino group, arylamino group, aryl group, arylthio Group, aryloxy group,
An aryl lower alkyl group or a heterocycle is shown. R ⁵ represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a benzoyl group, a heterocyclic carbonyl group, a heterocyclic methyl group or a tetrahydropyran-2-yl group. R ^{6 to} R ⁹ are hydrogen atom, halogen atom, trifluoromethyl group, lower alkyl group, lower alkoxy group, lower alkylthio group, hydroxy group, hydroxymethyl group, cyano group, carboxy group, formyl group, methylsulfinyl group, methyl A sulfonyl group, a methylsulfonyloxy group or a lower alkoxycarbonyloxy group is shown. R ⁷ together with R ⁶ or R ⁸ may form butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy. Z is-
O-, -S-, ethylene, vinylene, -CO-, -OC
HR ¹⁰ − or —SCHR ¹⁰ − is shown. R ¹⁰ represents a hydrogen atom or a lower alkyl group. X and Y each represent O, S or NH. YR ⁵ represents a lower alkylsulfinyl group or —OCH ₂ CH (OR ^c ) CH ₂ OR ^d . R ^a , R ^b ,
R ^c and R ^d each represent a hydrogen atom or a lower alkyl group. R ^c and R ^d each represent methylene, ethylene or isopropylidene. n is 1, 2, or 3. The compound represented by the formula (1), which is a prophylactic and / or therapeutic agent according to (1), and (19) a compound having an endothelin receptor antagonistic activity,

[0033]

[Chemical 15]

(In the formula, A ¹ is a group represented by the formula R ¹¹ —CO— (R ¹¹ is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a group represented by the formula Ar ^1- (CH ₂ ) p- Group (Ar ¹ represents a phenyl group, a furyl group or a thienyl group, p represents 0, 1 or 2), 1,3-dithio-2-ylidenemethyl group, or 1,3-dithiol-2-ylidene. (Lower alkoxycarbonyl) methyl group), a group represented by the formula R ¹² O—CO— (R ¹² represents a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, or a phenyl group), a formula ^{R 13 R 14 N-C (} = X1) - group (X1 represented by represents an oxygen or sulfur atom, R ¹³ is a lower alkoxycarbonyl group, a cycloalkyl group, a lower alkynyl group, a 1-adamantyl group, Pi Rijino group, piperidino group, perhydro azepin-1-yl group, perhydro azo Shin-1-yl group, perhydro azo Nin-1-yl group,
Alternatively, a group represented by the formula Ar ² — (CH ₂ ) q— (Ar ²
Represents a phenyl group (wherein one or two hydrogen atoms on the benzene ring may be substituted with a halogen atom, a lower alkyl group or a lower alkoxy group, respectively), a furyl group or a thienyl group, and q is 0, 1 or 2 is shown. ) Is shown. R
¹⁴ is a hydrogen atom, a hydroxyl group, a cycloalkyl group, or the formula _{^{Ar 3 - (CH 2) r-}} (Ar 3 represents a phenyl group, a furyl group or a thienyl group, r is 1 or 2.)
R ¹³ and R ¹⁴ together with the adjacent nitrogen atom may form a 5- to 9-membered nitrogen-containing saturated heterocycle having 4 to 8 carbon atoms, and the heterocycle is formed. In the methylene group, one methylene group which is not adjacent to a nitrogen atom may be substituted with an oxy group, a thio group or a group represented by the formula —NR ¹⁵ — (R ¹⁵ is a lower alkyl group). 1 to 4 hydrogen atoms on a carbon atom of the ring may be substituted with a hydroxyl group or a lower alkyl group which may be substituted with hydroxyl, and further, two adjacent carbon atoms in the heterocycle may be replaced with each other. Atoms may form double bonds or benzofused rings. Also, R ¹³ and R
¹⁴ is a formula (LII) with B)

[0035]

[Chemical 16]

(Wherein R ¹⁶ represents a hydrogen atom, a lower alkyl group or a cycloalkyl group, and R ¹⁷ and R ¹⁸ each independently represent a hydrogen atom or a lower alkyl group). B represents an oxygen atom or a group represented by the formula —NR ² — (R ² represents a hydrogen atom or a methyl group), or forms a group represented by the above formula (LII) together with A 1. R
³ represents a lower alkyl group having 3 to 5 carbon atoms. R ⁴ represents a hydrogen atom or a methyl group. R ⁵ is a 3-indolylmethyl group, a (2,3-dihydro-2-oxo-3-indolyl) methyl group, and the indole ring has the formula R at the 1-position.
_{^{51 -CO- (CH 2) s- (}} R 51 is a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a benzyloxy group, an amino group or a mono-lower alkylamino group, s is 0 to 6 integer And when s is 0, R ⁵¹ represents a group other than a hydroxyl group) or a formula (R ⁵²
_{O) 2 P (= O)} - (CH 2) t- (R 52 represents a hydrogen atom, a lower alkyl group or a benzyl group, t is substituted with a group represented by showing) an integer of 0-6. 3-indolylmethyl group, any hydrogen atom on the benzene ring is represented by the formula R ⁵³ O
A benzyl group optionally substituted with a group represented by —CO— (CH ₂ ) u— (R ⁵³ represents a hydrogen atom or a lower alkyl group, and u represents an integer of 0 to 6), and on the benzene ring A benzyl group in which one or two hydrogen atoms of is substituted with a hydroxyl group, or two hydrogen atoms on the benzene ring are substituted with a hydroxyl group and a sulfo group,
A benzothienylmethyl group, a (1-oxo-3-benzothienyl) methyl group or a (1,1-dioxo-3-benzothienyl) methyl group. X ² represents an oxygen atom or a sulfur atom. A ² is the formula (LIII), (LIV), (LV),
Shows a group selected from the group consisting of (LVI), (LVII) and (LVIII).

[0037]

[Chemical 17]

Y is a sulfo group, a phosphono group, or a formula --CO ₂ R
A group represented by ⁹¹ (R ⁹¹ represents a hydrogen atom, a lower alkyl group or a benzyl group) or a formula —CONR ⁹² R ⁹³ (R ⁹²
Represents a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group, a phenylsulfonyl group in which any of 1 to 5 hydrogen atoms on the benzene ring may be substituted with a lower alkyl group or a halogen atom, or a carboxymethyl group. .. R ⁹³ represents a hydrogen atom or a lower alkyl group. )
Represents a group represented by. R ⁶¹ represents a hydrogen atom or a lower alkyl group, or represents a methylene group together with R ⁷¹ . R ⁷¹ is a hydrogen atom, a lower alkyl group optionally substituted with a hydroxyl group, a phenyl group, a thienyl group, or a phenyl lower alkyl group in which any hydrogen atom on the benzene ring may be substituted with a hydroxyl group or a benzyloxy group. Group, thienyl lower alkyl group, thiazolyl lower alkyl group, 4-imidazolylmethyl group, (lower alkyl-substituted 4-imidazolyl) -methylthiomethyl group, 3-indolylmethyl group, carbamoyl lower alkyl group or N-benzyloxycarbonyl-ω -Amino lower linear alkyl group, or methylene group together with R ⁶¹ . However, when R ⁶¹ is a lower alkyl group, R ⁷¹ represents a group other than a hydrogen atom. ] The preventive and / or therapeutic agent according to (1), which is a compound represented by:

(20) An endothelin receptor antagonist compound has the formula [M] AA ¹ -AA ² -AA ³ -AA ⁴ -AA ⁵ -AA ⁶ [M] (wherein AA ¹ is D-Dip, D-Bip , D-His, D-His
(Dnp), D-2-Nal, D-1-Nal, D-Phe, D-Pg
l, D-Tyr, D-Tyr (OMe), D-Tyr (OEt), D-Tyr (Ot
Bu), D-Trp, D-Trp (For), D-Tic, D-Tza, D-
Pyr, Ac-D-Dip, Ac-D-Bip, Ac-D-His, Ac-D
-His (Dnp), Ac-D-2-Nal, Ac-D-1-Nal, Ac-
D-Phe, Ac-D-Pgl, Ac-D-Tyr, Ac-D-Tyr (OM
e), Ac-D-Tyr (OEt), Ac-D-Tyr (OtBu), Ac-D-T
rp, Ac-D-Trp (For), Ac-D-Tic, Ac-D-Tza, Ac
-D-Pyr, Ada-D-Dip, Ada-D-Bip, Ada-D-Hi
s, Ada-D-His (Dnp), Ada-D-2-Nal, Ada-D-
1-Nal, Ada-D-Phe, Ada-D-Pgl, Ada-D-Ty
r, Ada-D-Tyr (OMe), Ada-D-Tyr (OEt), Ada-D-
Tyr (OtBu), Ada-D-Trp, Ada-D-Trp (For), Ada-
D-Tic, Ada-D-Tza, Ada-D-Pyr, Adoc-D-Di
p, Adoc-D-Bip, Adoc-D-His, Adoc-D-His (Dn
p), Adoc-D-2-Nal, Adoc-D-1-Nal, Adoc-D
-Phe, Adoc-D-Pgl, Adoc-D-Tyr, Adoc-D-Tyr
(OMe), Adoc-D-Tyr (OEt), Adoc-D-Tyr (OtBu), Ad
oc-D-Trp, Adoc-D-Trp (For), Adoc-D-Tic, Ad
oc-D-Tza, Adoc-D-Pyr, Boc-D-Dip, Boc-D
-Bip, Boc-D-His, Boc-D-His (Dnp), Boc-D-
2-Nal, Boc-D-1-Nal, Boc-D-Phe, Boc-D-
Pgl, Boc-D-Tyr, Boc-D-Tyr (OMe), Boc-D-Tyr
(OEt), Boc-D-Tyr (OtBu), Boc-D-Trp, Boc-D-
Trp (For), Boc-D-Tic, Boc-D-Tza, Boc-D-Py
r, Z-D-Dip, Z-D-Bip, Z-D-His, Z-D-
His (Dnp), Z-D-2-Nal, Z-D-1-Nal, Z-D
-Phe, Z-D-Pgl, Z-D-Tyr, Z-D-Tyr (OM
e), Z-D-Tyr (OEt), Z-D-Tyr (OtBu), Z-D-T
rp, Z-D-Trp (For), Z-D-Tic, Z-D-Tza, Z
-D-Pyr, Fmoc-D-Dip, Fmoc-D-Bip, Fmoc-D
-His, Fmoc-D-His (Dnp), Fmoc-D-2-Nal, Fmoc
-D-1-Nal, Fmoc-D-Phe, Fmoc-D-Pgl, Fmoc
-D-Tyr, Fmoc-D-Tyr (OMe), Fmoc-D-Tyr (OE
t), Fmoc-D-Tyr (OtBu), Fmoc-D-Trp, Fmoc-D-
Trp (For), Fmoc-D-Tic, Fmoc-D-Tza or Fmoc-
D-Pyr is shown. AA ² is Ala, Alg, Arg, Asn, Asp, Da
b, Glu, Gln, Gly, homoArg, homoGlu, homoLys, Ile,
Leu, D-Leu, Lys, Met, Met (O), Met (O ₂ ), Nva, Nl
Indicates e, Orn, Phe, Tyr or Val or lacks AA ² . AA ³ is Asn, Asp, D-Asp, N-MeAsp, Glu, Gl
n, homoPhe, Phe or Tyr, or lacking AA ³ . AA ⁴ is Ala, Chx, Gly, Glu, Ile, D-Ile, Le
Indicates u, Nle, Nva or Val or lacks AA ⁴ . AA ⁵ is Ala, Chx, Gly, Ile, D-Ile, Leu, Nle,
Indicates Nva or Val or lacks AA ⁵ . AA ⁶ is 2-Nal, 1-Nal, Pyr, Trp, Tyr (OMe), Tyr (OEt), Ty
r (OtBu), Tyr, Trp-Gly, Trp-Asp, Trp (For), Dip, P
he, Bza or

[0040]

[Chemical 18]

Is shown. The preventive and / or therapeutic agent according to claim 1, which is a compound represented by the formula (4) or a pharmaceutically acceptable salt thereof.

(21) The endothelin receptor antagonist compound has the formula [N]

[0043]

[Chemical 19]

(In the formula, R ₁ is —X (CH ₂ ) nAr, —X
(CH ₂ ) nR ₈ or

[0045]

[Chemical 20]

R ₂ is hydrogen, Ar or (c)
P ₁ is —X (CH ₂ ) nR ₈ ; P ₂ is —X (C
H ₂₎ nR be ₈ or -XR ₉ Y; R ₃ and R ₅ are each independently hydrogen, R _11, OH, C _1-8 alkoxy, S (O) _q
R ₁₁ , N (R ₆ ) ₂ , Br, F, I, Cl, CF ₃ , NHC
OR _6, -XR ₉ Y or -X (CH ₂₎ nR ₈ [wherein -
The methylene group of X (CH ₂ ) nR ₈ has 1 or more-
(CH ₂ ) nAr group may be substituted]; R ₄ hydrogen, R ₁₁ , OH, C _1-5 alkoxy, S (O)
_{q represents} R ₁₁ , N (R ₆ ) ₂ , —X (R ₁₁ ), Br, F, I, Cl or NHCOR ₆ , wherein C _1-5 alkoxy is substituted with OH, methoxy or halogen. R ₆ independently represents hydrogen or C _1-4 alkyl; R ₇ independently represents hydrogen or C _1-6 alkyl or (CH ₂ ) nAr; R ₈ represents hydrogen, R ₁₁ , C
Represents OOH, PO ₃ H ₂ , P (O) (OH) R ₇ or tetrazole; R ₉ is C _1-10 alkyl, C _2-10 alkenyl or phenyl, all of which are one or more OH, N (R ₆ ) ₂ , COOH, halogen or XC _1-5
R ₁₀ is R ₃ or R ₄ ; R ₁₁ is C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, which are all 1 or it May be substituted with the above OH, CH ₂ OH, N (R ₆ ) ₂ or halogen; X is (CH ₂ ) n, O, N
R ₆ or S (O) _q ; Y is CH ₃ or —CH ₂ X
(CH ₂ ) nAr; Ar is

[0047]

[Chemical 21]

Naphthyl, indolyl, pyridyl or thienyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, pyropyridylyl, piperidylyl, piperidylyl, piperidylyl, piperidylyl, piperidylyl, piperidylyl, piperidylyl, piperazinyl, piperazinyl Can be substituted with one or more R ₃ or R ₄ groups; A is C═O or [C (R ₆ ) ₂ ] m; B
Is —CH ₂ — or —O—; Z ₁ and Z ₂ are each independently hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C
_2-8 alkynyl, OH, C _1-8 alkoxy, S (O) _q C _1-8
Alkyl, N (R ₆ ) ₂ , Br, F, I, Cl, NHCOR
_{6, -X (CH 2) nR} 8, phenyl, benzyl or C _3-6
Represents cycloalkyl, wherein C _1-8 alkyl, C
_2-8 alkenyl, C _2-8 alkynyl is COOH, OH, C
O (CH ₂ ) nCH ₃ , CO (CH ₂ ) nCH ₂ N (R ₆ ) ₂ or halogen can be substituted; or, Z ₁ and Z ₂ are bonded together by adjacent carbon atoms. -O-
It is also possible to form the A-O-; Z ₃ is Z ₁ or X
R ₉ Y; q is 0, 1 or 2; n is an integer from 0 to 6; m is 1, 2 or 3; a dotted line indicates a possible double bond; or these A pharmaceutically acceptable salt of, having the following limitations. R ₂ is not hydrogen when X is S (O) _q ; only one R ₁₀ is present and P ₁ is absent when a double bond is present; the compound of formula I is (1RS) -1,3 -Diphenylindene-2-carboxylic acid; (cis, cis)-(1RS, 3SR)
-1,3-diphenylindan-2-carboxylic acid; (1RS)
-3- [3-Methyl-1-phenyl- (1H) -indo-2-en-1-yl] propionic acid; or (1RS) -2- [1,3-diphenyl- (1H) -indo-2 -En-1-yl] Not ethanoic acid. The preventive and / or therapeutic agent according to (1), which is a compound represented by: or a pharmaceutically acceptable salt thereof.

(22) The endothelin receptor antagonist compound has the formula [O] AA ¹ -AA ² -AA ³ -AA ⁴ -AA ⁵ -AA ⁶ [O] (where AA ¹ is

[0050]

[Chemical formula 22]

Wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
Aryl, heteroaryl, fluorenylmethyl methyl, -N (R ³⁾ R ² (wherein R ² and R ³ are each the same or different, each represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl , Arylalkyl, heteroaryl or fluorenylmethyl), COOR ² (wherein R ² is as defined above) —OR ² (wherein R ² is as defined above) —NR ^2- C (O) NR ² R ³ (wherein R ² and R ³ are as defined above) —COC (R ⁹ ) ₃ (wherein R ⁹ is F, Cl, Br or I) --CH ₂ --OR ² (wherein R ² is as defined above) --N (R ^2a )-C (O) OR ³ (wherein R ^2a and R ³ are R ³ except in the case of hydrogen is as defined above) or COR ² ( Among, R ² is as a is) R ¹ defined above is hydrogen or alkyl, Z is -O-, -S (O) m- (wherein m is 0 or an integer of 1 or 2) , -NR ^2- (wherein R ² is as defined above)-(CH ₂ ) n- (where n is zero or an integer of 1, 2, 3 or 4),-( _{CH 2) n-CH = CH-} (CH 2) n- ( wherein, n is as defined above), - CO-, -C (oR 2) R 1 - ( wherein, R ¹ and R ² is as defined above), or —R ² CR ³ —, wherein R ² and R ³ are each the same or different and are each as defined above, X and Y Are the same and are substituted at the same position on the aromatic ring, each being 1, 2, 3 or 4 substituents selected from the following group: Hydrogen, halogen, alkyl, COOR ² (in the formula,
R ² is as defined above, —CON (R ² ) R ³ (wherein R ² and R ³ are as defined above), —N (R ³ ) R ² (wherein , R ² and R ³ are as defined above), or nitro, or

[0052]

[Chemical formula 23]

Where R, Z, X and Y are as defined above. AA ² is

[0054]

[Chemical formula 24]

(Wherein R ⁴ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, —N (R ^2b ) R ^3b (wherein R ^2b and R ^3b are the same or different, each hydrogen, alkyl, cycloalkyl, aryl or heteroaryl), in -OR ^2b (wherein, R ^2b are as defined ^{above), -CON (R 2b) R} 3b ( wherein, R ^2b And R ^3b are the same or different and are as defined above), —COR ^2b (wherein R ^2b is as defined above), —NH—C (NH) —NH—R ^2b (Wherein R ^2b is as defined above), —COOR ^2b (wherein R ^2b is as defined above), R ¹ and n are as defined above, AA ² Is absent; AA ³ is

[0056]

[Chemical 25]

(Wherein R ⁵ is hydrogen, alkyl, aryl, heteroaryl, —CON (R ^2b ) R ^3b (wherein R ^2b and R ^3b are the same or different and are as defined above). ), -COR ^2b (wherein R ^2b is as defined above), -COOR ^2b (wherein R ^2b is as defined above), R ¹ and n are as defined above. AA ³ is absent; AA ⁴ and AA ⁵ are each independently absent or each independently

[0058]

[Chemical formula 26]

Wherein R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl, R ¹ and n are as defined above, AA ⁶ is

[0060]

[Chemical 27]

Wherein R ⁷ is aryl or heteroaryl, R ⁸ is —COOR ¹ (wherein R ¹ is as defined above), —OR ¹ (wherein R ¹ is as defined above) --C (O) N (R ¹ ) R ¹ (wherein R ¹ is as defined above) --CH ₂ --OR ¹ (wherein R ¹ is as defined above) R ¹ and n are as defined above; AA ¹ , A
The stereoisomerism of C * in A ² , AA ³ , AA ⁴ or AA ⁵ is D, L, or DL, and the stereoisomerism of C * in AA ⁶ is L; or a pharmacologically acceptable salt thereof. The preventive and / or therapeutic agent according to certain (1).

(23) The endothelin receptor antagonist compound has the formula [P] XA-Trp-B-Gly-Thr-E-GY (P) (wherein A represents Asn or Asp, and B represents His
Or Lys, E represents Ala or Ser, G represents Ala or Pro, and X represents X ¹ -Gl.
y or

[0063]

[Chemical 28]

And Y is hydroxy, lower alkoxy, amino,

[0065]

[Chemical 29]

Or

[0067]

[Chemical 30]

[Wherein X ¹ and X ³ represent hydrogen, benzyloxycarbonyl, t-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or a carbonyl-substituted or unsubstituted lower alkanoyl, and X ² And Y ² represents hydrogen, Y ¹ represents hydroxy, lower alkoxy or amino, or X
¹ , Y ¹ and X ² , Y ² together are X ¹ -Y ¹
And X ² -Y ² represent a single bond, Z is hydroxy, lower alkoxy, benzyloxy, or benzhydryloxy, Gly-Z ¹ (in the formula, Z ¹ is hydroxy, lower alkoxy, benzyloxy, or benzhidyl. Represents a drilloxy or, together with X ¹ , X ¹ -Z ¹ represents a single bond), Ala-Z ¹ (in the formula, Z ¹ is as defined above), Val-Z ¹ (in the formula: , Z ¹ is as defined above),
Trp-Z ¹ (wherein Z ¹ has the same meaning as above), Trp
-Gly-Z ¹ (wherein Z ¹ has the same meaning as above), Tr
p-Asn-Tyr-Tyr-Trp-Z ¹ (in the formula, Z ¹
Is as defined above), Trp-Phe-Phe-As
n-Tyr-Tyr-7Hyt-Z ¹ (wherein Z ¹ is as defined above, 7Hyt represents 7-hydroxytryptophan), Trp-Ile-Ile-Trp-Z
¹ (in the formula, Z ¹ has the same meaning as above), Trp-Val-
Tyr-Phe-W-His-Leu-Asp-Ile
-Ile-Trp-Z ¹ (wherein Z ¹ has the same meaning as above, W represents Ala, Ser or Cys), Tr
p-W-His-Leu-Asp-Ile-Ile-T
rp-Z ¹ (wherein Z ¹ and W have the same meanings as described above),
Trp-Val-Tyr-Tyr-W-His-Leu
-Asp-Ile-Ile-Trp-Z ¹ (wherein Z ¹ and W have the same meanings as described above), Trp-Leu-Tyr.
-Phe-W-His-Gln-Asp-Val-Il
e-Trp-Z ¹ (wherein Z ¹ and W are as defined above), Trp-Val-Tyr-Phe-W-Phe-
Phe-Asn-Tyr-Tyr-Trp-Z ¹ (wherein
Z ¹ and W are as defined above, and Trp-Phe-
Phe-Asn-Tyr-Tyr-W-His-Leu
-Asp-Ile-Ile-Trp-Z ¹ (wherein Z ¹ and W have the same meanings as described above), Trp-Phe-Phe
-Asn-Tyr-Tyr-Asn-Ile-Ile-
Trp-Z ¹ (in the formula, Z ¹ has the same meaning as described above), or J-Phe-M-Q-Tyr-R-T-Z ¹ (in the formula, J is Trp or a single bond, M is Phe or Single bond, Q is Asn or single bond, R is Tyr or single bond, T is Trp, Ala, Phe, Tyr, Trp-T.
rp, Asn-Tyr-Tyr-Trp, Trp-As
n-Tyr-Tyr-Trp, Trp-Val-Tyr
-Phe-W-His-Leu-Asp-Ile-Il
e-Trp (wherein W has the same meaning as defined above) or a single bond, and at least 2 of J, M, Q, R and T
One or more do not represent a single bond at the same time, and Z ¹ has the same meaning as above)]}, or a pharmacologically acceptable salt thereof, (1) The preventive and / or therapeutic agent.

(24) A peptide derivative whose endothelin receptor antagonist compound is [Q]

[0070]

[Chemical 31]

(Wherein A is a group of the formula R ¹¹ O—CO— (wherein R ¹¹ is a lower alkyl group or a phenyl group), or a group of the formula R ¹²
R ¹³ N—C (═O) — (wherein R ¹² is a lower alkyl group, a cycloalkyl group, a 1-adamantyl group, or 1 of its benzene ring.
Or a desired hydrogen atom of 2 is independently a phenyl group which may be substituted with a halogen element, a trifluoromethyl group, a nitro group, an amino group or a formylamino group, a pyridyl group or a thienyl group, and R ¹³ is hydrogen. An atom, a lower alkyl group or a cycloalkyl group, or R ¹² and R ¹³ together with their adjacent nitrogen atoms are 5 to 9 membered and 4 to
A nitrogen-containing saturated heterocycle having 8 carbon atoms, wherein in the methylene group forming the ring, one desired methylene group not adjacent to the above nitrogen atom is changed to a thio group. Wherein 1 to 4 hydrogen atoms of the carbon atoms of the heterocycle can each independently be changed to a lower alkyl group, and two adjacent carbon atoms of the heterocycle form a benzofused ring. B is an oxygen atom or a formula —NR ² group (wherein R ² is a hydrogen atom or a lower alkyl group), R ³ is a lower alkyl group, a cycloalkyl group, an aryl group, a heterocyclic group, A cycloalkyl lower alkyl group, an aryl lower alkyl group or a heterocyclic lower alkyl group, X ¹ is an oxygen atom or a formula —NR ⁴ group (in the formula, R
⁴ is a hydrogen atom or a lower alkyl group), and R ⁵ is 3-
An indolylmethyl, 3-benzothienylmethyl, 1-naphthylmethyl or benzyl group, wherein 1 on the ring
Alternatively, 2 desired hydrogen atoms are substituted with a hydroxyl group, a halogen group, a formyl group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkoxycarbonyl group, or a nitro group. Or a compound represented by the formula R ⁵¹ —CO—X ² (wherein R ⁵¹ is a lower alkyl group, a lower alkoxy group, or an amino group which may be substituted with a lower alkyl group, and X ² is an oxygen atom). Or formula-N
R ⁵² — (wherein R ⁵² is a hydrogen atom or a lower alkyl group)
And X ³ is an oxygen atom or a sulfur atom, and R ⁶ may have a hydrogen atom or a substituent selected from the group consisting of a hydroxyl group, a lower alkoxy group, a lower alkylthio group and a heterocyclic group. A lower alkyl or lower alkenyl group, n is 0 or 1, Y is a hydroxymethyl group, a formula CO ₂ R ⁷¹ (wherein R ⁷¹ is a hydrogen atom or a lower alkyl group), a formula CONHR ⁷² (wherein R ⁷² Is a hydrogen atom, or a lower alkyl group optionally having a substituent selected from the group consisting of a hydroxyl group, a carboxyl group and a sulfo group), a 1H-tetrazol-5-yl group, a sulfo group and a phosphono group, or The prophylactic and / or therapeutic agent according to (1), which is a pharmacologically acceptable salt thereof.

(25) The endothelin receptor antagonist compound has the formula [R]

[0073]

[Chemical 32]

[Wherein R ¹ is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aralkyl group, an aryl group, a 5- to 10-membered heterocyclic group or a 5- to 10-membered heterocyclic lower alkyl group ( The lower alkyl group, cycloalkyl group, cycloalkyl lower alkyl group, aralkyl group, aryl group, 5- to 10-membered heterocyclic group and 5- to 10-membered heterocyclic lower alkyl group are each independently on their chain. And / or a lower alkyl group on the ring, a halogen atom,
Hydroxyl group, lower alkoxy group, nitro group, trifluoromethyl group, cyano group, formyl group, lower alkanoyl group,
Carboxyl group, lower alkoxycarbonyl group, amino group, mono-lower alkylamino group, di-lower alkylamino group, formylamino group, alkanoylamino group, aroylamino group, carbamoyl group, N-mono-lower alkylcarbamoyl group or N, N-di Lower alkylcarbamoyl group, mercapto group, lower alkylthio group or lower alkanoylthio group may be present); p is 0 to 2
R ¹ is a single bond or a divalent lower alkylene group optionally substituted with a lower alkyl group; R ²
Is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aralkyl group, an aryl group, 5 to 10
Membered heterocyclic group or a 5- to 10-membered heterocyclic lower alkyl group; X ¹ is an oxygen atom or a formula: —NR ³ — [wherein R ³ represents a hydrogen atom or a lower alkyl group] R ⁴ is a 5- to 10-membered heterocyclic lower alkyl group [said 5 to
The 10-membered heterocyclic lower alkyl group is a lower alkyl on the ring or has the formula: R ⁴¹ —CO— (CH ₂ ) _q — (wherein R ⁴¹ is a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, Aralkyloxy group, amino group, mono-lower alkylamino group or di-lower alkylamino group; q is 0 to
A group represented by the formula 6)] or an aryl lower alkyl group [wherein the aryl lower alkyl group has a nitro group on its ring, a compound represented by the formula: R ⁴² —CO— (CH ₂ ). _r
-(In the formula, R ⁴² is a lower alkyl group, a lower alkoxy group,
A group represented by an amino group, a mono-lower alkylamino group or a di-lower alkylamino group, and r represents an integer of 0 to 6, a compound represented by the formula: R ⁴² —COX ² — (wherein R ⁴² is as defined above). Has the meaning, X ² is an oxygen atom or the formula: —NR ⁴³ — (wherein R 2
⁴³ group or the formula is represented by a hydrogen atom or a lower alkyl _{^{group): R 44 O- (CH 2}} ) s - ( wherein, R ⁴⁴ represents a hydrogen atom or a lower alkyl group, s is 0 to 6 Represents an integer)
May have a group represented by]; X ³ represents an oxygen atom or a sulfur atom; A ² represents the following general formula [RII]
An arbitrary group selected from the group consisting of groups represented by [RVII] is shown.

[0075]

[Chemical 33]

[Wherein Y is a hydroxy lower alkyl group,
Sulfo group, phosphono group, formula: —CO ₂ R ⁸¹ (in the formula, R ⁸¹
Represents a hydrogen atom or a carboxy protecting group) or a formula: —CONR ⁸² R ⁸³ (wherein R ⁸² and R ⁸³ are each independently a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group, a benzene ring) R represents a group represented by any of the above 1 to 5 hydrogen atoms independently represents a lower alkyl group or a phenylsulfonyl group optionally substituted with a halogen atom or a carboxy lower alkyl group; R
⁵¹ represents a hydrogen atom or a lower alkyl group, or R
Together with ⁶¹ represents a methylene group; R ⁵³ , R ⁶¹ and R
⁶² are each independently a hydrogen atom, a lower alkyl group, a lower alkenyl group, an aryl group, an aryl lower alkyl group, 5
10-membered heterocyclic group or 5- to 10-membered heterocyclic lower alkyl group (the lower alkyl group, lower alkenyl group, aryl group, aryl lower alkyl group, 5- to 10-membered heterocyclic group and heterocyclic lower alkyl group) Are each independently a hydroxyl group, a lower alkyl group, a halogen atom, a lower alkoxy group, an aryloxy group, an acyloxy group, a carboxyl group, a protected carboxyl group on their chain and / or ring.
Having an amino group, monoalkylamino group, di-lower alkylamino group, carbamoyl group, N-mono-lower alkylcarbamoyl group, N, N-di-lower alkylamino group, lower alkoxycarbonylamino group or aryloxycarbonylamino group R ⁶¹ is R ⁵¹
And R ⁶² may represent a methylene group together with R ⁵² below (provided that when R ⁵¹ represents a lower alkyl group, R ⁶¹ represents a hydrogen atom other than hydrogen atom). When R ⁵² represents a group other than a hydrogen atom,
R ⁶² represents a hydrogen atom or a lower alkyl group); R ⁵² represents a hydrogen atom, an aryl group, an aralkyl group, a carboxyl group,
Carbamoyl, N- mono-lower alkylcarbamoyl group, N, N- di-lower alkylcarbamoyl group or N- arylcarbamoyl or shown, or represents a single bond together with R ^7; R ⁷ is a hydrogen atom, Represents a lower alkyl group, a lower alkoxy group, a hydroxyl group, or, together with R ⁵² , represents a single bond, t represents an integer of 2 to 6; Z represents C
H or N is shown; v is an integer of 1 to 3]] or a pharmaceutically acceptable salt thereof, and the prophylactic and / or therapeutic agent according to (1).

(26) The endothelin receptor antagonist compound has the structural formula

[0078]

[Chemical 34]

The preventive and / or therapeutic agent according to (25), which is a compound represented by: or a pharmaceutically acceptable salt thereof. (27) The endothelin receptor antagonist compound has a structural formula [S] cyclo (-Dtrp ( COOCH ₃ ) -DAsp-Pro-DtertLeu-γMeLeu-) [S] The preventive and / or therapeutic agent according to (1), which is a cyclic pentapeptide represented by [S] and a related compound or a pharmaceutically acceptable salt thereof. .

(28) The endothelin receptor antagonist compound has the formula [T]

[0081]

[Chemical 35]

Wherein ^{one of} X and Y is N and the other is O; R is naphthyl or R ¹ , R ² and R ³
Naphthyl substituted with R ¹ , R ² and R ³
Are independently hydrogen; alkyl, alkenyl, alkynyl,
Alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, all of which are Z ¹ , Z ²
And Z ³ ; halo; hydroxyl; cyano; nitro; -C
(O) H; -C (O) R ⁶ ; CO ₂ H; CO ₂ R ⁶ ; -SH; -S
^{(O) nR 6; -S (} O) m-OH; -S (O) m-OR 6; -OS (O)
^{m-R 6; -OS (O} ) m-OH; -OS (O) m-OR 6; -Z 4 -N
R ⁷ R ⁸ ; or -Z ⁴ -N (R ¹¹ ) -Z ⁵ -NR ⁹ R ¹⁰ may be substituted; R ⁴ and R ⁵ are independently hydrogen; alkyl, alkenyl, alkynyl, alkoxy, Cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, all of which are Z ¹ , Z ² and Z ³ ; halo; hydroxyl; cyano; nitro; --C (O) H; O) R ⁶ ;
CO ₂ H; CO ₂ R ⁶ ; -SH; -S (O) nR ⁶ ; -S (O) m-O
H; -S (O) m- OR 6; -OS (O) m-R 6; -OS (O) m-O
H; -OS (O) m-OR ⁶ ; -Z ⁴ -NR ⁷ R ⁸ ; or -Z ⁴ -N
(R ^{1 1} ) -Z ⁵ —NR ⁹ R ¹⁰ may be substituted; or R ⁴ and R ⁵ may be joined together to form an alkylene or alkenylene, any of which may be Z ¹ , Z ² or Z. ³ ), which together with the adjacent carbon atoms complete a 4-8 membered saturated, unsaturated or aromatic ring; R ⁶ is alkyl, alkenyl , Alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z ¹ , Z ² or Z ³ ; R ⁷ Is defined as R ⁶ , or hydrogen, hydroxyl, cyano, —C (O) H, —C (O) R ⁶ , CO
₂ R ⁶ ; or when Z is not SOn, R ⁷ is —SH, CO
R ⁶ , -S (O) m-OH, -S (O) m-OR ⁶ , -OS (O) m-
R ⁶ , —OS (O) m—OH or —OS (O) m—OR ⁶ ; R ⁸ is R ⁶
Or hydrogen, or when Z ⁴ is not CO and R ⁷ is not COH, —C (O) R ⁶ or CO ₂ R ^6, R ⁸ is COH, —C (O) R ⁶ ; Or NR ⁷ R ⁸ is alkylene or alkenylene (Z ¹ , Z ² or Z respectively)
Optionally substituted with ³ ) to form a saturated, unsaturated or aromatic 3-8 membered ring; R ⁹ is as defined for R ⁶ or hydrogen, hydroxyl, —C (O) H , -C (O) R
⁶ , CO ₂ R ⁶ ; -SH, SOnR ⁶ , -S (O) m-OH, -S
(O) m-OR ⁶ , -OS (O) m-R ⁶ , -OS (O) m-OH or-
OS (O) m-OR ⁶ ; R ¹⁰ is as defined for R ⁶ , or hydrogen, or Z ⁵ is not CO, R ⁹ is COH, —C
(O) When R ⁶ or CO ₂ R ⁶ is not R ¹⁰ is COH or-
Can be C (O) R ⁶ ; R ¹¹ is as defined for R ⁶ or is hydrogen, hydroxyl, —C (O) H, —C
(O) R ⁶ or CO ₂ R ⁶ , or _{two of} R ⁹ , R ¹⁰ and R ¹¹ are alkylene or alkenylene (optionally substituted with Z ¹ , Z ² or Z ³ respectively) Form a saturated, unsaturated or aromatic 3-8 membered ring with adjacent atoms; Z ¹ , Z ² and Z ³ are H, halogen, hydroxyl, alkyl, alkenyl, aralkyl, alkoxy, aryloxy, Aralkyloxy, -SH, -S (O) nZ ⁶ , -S (O) m-OH, -S (O) m-O
Z ⁶ , -OS (O) m-OH, -OS (O) m-OZ ⁶ , oxo, cyano, nitro, -C (O) H, -C (O) Z ⁶ , CO ₂ H, CO
₂ Z ⁶ , Z ⁴ NZ ⁷ Z ⁸ , Z ⁴ NZ ¹¹ Z ⁵ Z ⁶ , Z ⁴ NZ ¹¹ Z ⁵ N
Z ⁷ Z ⁸ ; Z ⁴ and Z ⁵ are vinyl bonds, Z ⁹ SOnZ ¹⁰ and Z ⁹ C
OZ ¹⁰ , Z ⁹ CSZ ¹⁰ , Z ⁹ OZ ¹⁰ , Z ⁹ SZ ¹⁰ or Z ⁹
OCOZ ¹⁰ ; Z ⁶ , Z ⁷ and Z ⁸ are H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl; or NZ ⁷ Z ⁸ is saturated with alkylene or alkenylene, Form an unsaturated or aromatic 3- to 8-membered ring; Z ⁹ , Z ¹⁰ are single bonds, alkylene, alkenylene or alkynylene; Z ¹¹ is as defined for R ⁶ or hydrogen, hydroxyl, --C
(O) H, -C (O) Z ⁶ or CO ₂ Z ⁶ ; Z ⁷ , Z ⁸ and Z
Two of ¹¹ are alkylene or alkenylene, which are saturated, unsaturated or aromatic with the atoms to which they are adjacent 3 to 3
Forming an 8-membered ring; m = 1 to 2; n = 0, 1 or 2; a compound or a pharmaceutically acceptable salt thereof,
(1) The preventive and / or therapeutic agent according to (29), an endothelin receptor antagonist compound

[0083]

[Chemical 36]

The preventive and / or therapeutic agent according to (28), which is a compound which is: or a pharmaceutically acceptable salt thereof.

(30) The endothelin receptor antagonist compound has the formula [U]

[0086]

[Chemical 37]

Wherein Ar is a substituted or unsubstituted aromatic or heterocyclic ring; R is H or a substituted or unsubstituted straight chain, branched chain, cyclic or straight chain, branched chain, cyclic mixture. Is an alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxyalkyl or alkoxycarbonyl group having 1 to 20 carbon atoms; A is a functional group having a polar group, preferably CO
OH or RNH; R ₁ is R, R—C═O, R substituted with one or more heteroatoms, a substituted or unsubstituted aryl group, or aryl (CH ₂ ) n; R ₂ Is (CH ₂ ) n, CHR, C (R) ₂ , COO, OC
O, NHCO, CONH, SO, SO ₂ or NR; R ₃
And R ₄ are the same or different or absent and each is ═O, hydrogen, O-aryl, OR, O-alkyl or alkyl, aryl, SR, S-aryl, N
HR, NH-aryl, NR, or another heteroaromatic group; R ₅ is H, OH or R; E and F are the same or different and are N or (CH ₂ ) p; p is zero. Is an integer between 5 or 0; m and n are zero and 1
Is an integer between 0 or 0; T is O, S, NCOR
Or NR; U and V are the same or different and are (CH ₂ ) n; W is CO, (CH ₂ ) n, (CH ₂ ) n
-CHR or CHR- (CH ₂₎ be n; X and Y
Are the same or different and H, alkyl or aryl, or X and Y form a saturated or unsaturated mono- or heterocyclic ring of 3 to 15 members; Z is H, SR, NHR or N (R) ₂ . The preventive and / or therapeutic agent according to (1).

(31) An endothelin receptor antagonist compound

[0089]

[Chemical 38]

(30) The preventive and / or therapeutic agent according to (30), (32) The endothelin receptor antagonist compound has the formula [V]

[0091]

[Chemical Formula 39]

Wherein _{one of} X and Y is N and the other is O; R ₁ , R ₂ and R ₃ are independently hydrogen (R ₁ is not hydrogen); alkyl, alkenyl, alkynyl , Alkoxy, cycloalkyl (alkyl), cycloalkenyl (alkyl), aryl, aryloxy, aralkyl or aralkoxy; halo, OH, CN, NO ₂ ,
CHO, COR ₆ , CO ₂ H, CO ₂ R ₆ , -SH, -S (O)
nR ₆ , -S (O) m-OH, -S (O) m-OR ₆ , -OS (O) m-R
₆ , -OS (O) m-OH, -OS (O) m-OR ₆ , -Z ₄ -NR ₇ R
₈ or -Z ₄ -N (R ₁₁ ) -Z ₅ -NR ₉ R ₁₀ and R ₄ and R ₅ are the same as defined for R _{1 to} R ₃ or are bonded together to form 4 to Form an 8-membered saturated, unsaturated or aromatic ring; R ₄ is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,
Cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, all of which may be substituted with Z ₁ , Z ₂ and Z ₃ ; R ₇ is hydrogen; alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cyclo Alkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, all of which may be substituted with Z ₁ , Z ₂ and Z ₃ ; CN; OH; CHO, COR ₆ ; CO ₂
H, CO ₂ R ₆ ; -SH, when Z ₄ is not -S (O) m-
_{-S (O) nR 6, -S} (O) m-OH, -S (O) m-OR 6 or -
OS (O) m-OR ₆ ; R ₈ is hydrogen; when Z ₄ is not —C (O) — and R ₇ is not CHO, COR ₆ , CO ₂ H, CO ₂ R _6, CHO, COR ₆ ; alkyl , Alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, all of which are Z
¹ , Z ² and Z ³ may be substituted; or R ₇ and R ₈ are adjacent to each other by alkylene or alkenylene, which may be substituted by Z ¹ , Z ² or Z ³ , respectively. Form a saturated, unsaturated or aromatic 3-8 membered ring with the atoms present; R ₉ is hydrogen; hydroxyl;
CHO, COR ₆ ; CO ₂ H, CO ₂ R ₆ ; -SH, -S (O)
nR ₆ , -S (O) m-OH, -S (O) m-OR ₆ , -OS (O) m-R
₆ , -OS (O) m-OH or -OS (O) m-OR ₆ ; alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, which are Both can be substituted with Z ₁ , Z ₂ and Z ₃ ; R ₁₀ is hydrogen; Z ₅ is not —C (O) — and R ₉ is CHO, COR ₆ , CO ₂ H, CO ₂ When not R _6, it is CHO, COR ₆ ; alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, each of which is Z
¹ , R 2 can be substituted with Z ² and Z ³ ; R ₁₁ is hydrogen; one of R ₉ and R ₁₀ is hydroxyl, CO ₂ H,
Hydroxyl, CO ₂ H or CO _{2 when not} CO ₂ R ₆
R ₆ ; CHO, COR ₆ ; alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, all of which are Z
₁ , Z ₂ and Z ₃ may be substituted; or any two of R ₉ , R ₁₀ and R _{11 taken} together are alkylene or alkenylene (substituted by Z ₁ , Z ₂ or Z ₃ respectively). Optionally form a saturated, unsaturated or aromatic 3-8 membered ring with the adjacent atoms; Z ₁ , Z ₂ and Z ₃ are each independently H, halogen, hydroxyl, Alkoxy, -SH, -S (O) nZ ₆ ,
-S (O) m-OH, -S (O) m-OZ 6, -OS (O) m-OH or ^{-OS (O) m-OZ 6} ; oxo, cyano, nitro, -C
(O) H, -C (O) Z ₆ , CO ₂ H, CO ₂ Z ₆ , NZ ₇ Z ₈ ,
^{-C (O) NZ 7 Z 8} ; or ^{-S (O) mZ 7 Z 8} ; Z 4 and Z ₆ are each independently a single bond, -SOn-, CO, CS
Or Z ¹⁰ , Z ⁹ OZ ¹⁰ , Z ⁹ SZ ¹⁰ or Z ⁹ OCOZ
¹⁰ ; alkyl, alkenyl, alkynyl, alkoxy,
Cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, all of which may be substituted with Z ₁ , Z ₂ and Z ₃ ; any of R ₉ , R ₁₀ and R ₁₁ . Or two taken together are alkylene or alkenylene (which may be respectively substituted by Z ₁ , Z ₂ or Z ₃ ) Z ₆ , Z ₇ and Z ₈ are each independently H, alkyl, alkenyl, alkynyl, alkoxy , Cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, or Z ₇ and Z ₈ together are alkylene or alkenylene, with 3 to 8 membered saturated with adjacent nitrogen atoms,
Form an unsaturated or aromatic 3- to 8-membered ring; m = 1 to
2; n = 0, 1 or 2; a preventive and / or therapeutic agent according to (1), which is a phenylsulfonamide derivative, (33) an endothelin receptor antagonist compound

[0093]

[Chemical 40]

The preventive and / or therapeutic agent according to (32), which is

(34) The endothelin receptor antagonist compound has the formula [W1], [W2] or [W3]

[0096]

[Chemical 41]

X is an α-amino acid having a sterically constrained 4-16C side chain, Y is Ser and Z is an α-amino acid having a sterically constrained side chain. The side chain is a cyclic pentapeptide in which the C-amino and N-amino groups of X form one to three separate or fused rings having an amino group that is one member of the ring. The preventive and / or therapeutic agent described. (35) The endothelin receptor antagonist compound has the formula [X1],
[X2] or [X3]

[0098]

[Chemical 42]

The preventive and / or therapeutic agent according to (1), which is a compound of: In the above items (2) to (35), the items (2) to (6) are more preferable. Furthermore, the present invention relates to the following compounds. Cyclo (-D-Asp-Asp (R1) -Asp-D-Thg (2) -Leu-D-Trp-)
Disodium salt.

The salts of the above-mentioned compound having an endothelin receptor antagonistic action are also compounds having an endothelin receptor antagonistic action in the present invention. Preferable examples of the salt include pharmacologically acceptable salts of compounds having an endothelin receptor antagonistic action. Examples of the pharmacologically acceptable salt of the compound having an endothelin receptor antagonistic action include the above-mentioned alkali metal salts (eg sodium salt, potassium salt etc.), alkaline earth metal salts (eg calcium salt, magnesium salt etc.). ), Ammonium salt, organic base salt (eg, pyridine salt, triethylamine salt, etc.), inorganic acid salt (eg, hydrochloride, sulfate, nitrate, etc.), organic acid salt (eg, acetate, oxalate, paratoluene) Sulfonate etc.) is used. The salt of the compound having an endothelin receptor antagonistic action can be produced by a method known per se.

As the compound having an endothelin receptor antagonism in the present invention, any compound having an endothelin receptor antagonism can be used, and these may be known ones, and further, after the filing date of the present invention. It may be a compound having an endothelin receptor antagonistic action which is discovered or reported in. The compound may be any type as long as it has an endothelin receptor antagonistic action, such as a peptide, a protein and a chemically synthesized compound. The compound having an endothelin receptor antagonism may be any of compounds having an endothelin-1, endothelin-2 or endothelin-3 receptor antagonism, and particularly a compound having an endothelin-1 receptor antagonism. Is preferred. The compound having an endothelin receptor antagonism in the present invention also includes what is called an endothelin antagonist in the field of the present invention. Furthermore, there are A type (ETA receptor) and B type (ETB receptor) in the endothelin receptor,
The “endothelin receptor” used in the present invention includes both types. Specific examples of the compound having an endothelin receptor antagonistic action in the present invention include, for example, Japanese Patent Application No. 4-216019 (EP-A-52).
8, 312), Japanese Patent Application No. 4-344252 (EP-A-5).
52,489), Japanese Patent Application No. 4-27785 (EP-A-4).
99,266), Japanese Patent Application No. 3-503831 (WO91 /
13089), EP-A-436,189, EP-A-.
457,195, EP-A-510,526, 92/12
991, JP-A-4-288099, EP-A-496,
452, EP-A-526, 708, EP-A-46
0,679 or the compounds described in WO92 / 20706 are used. Further, as a compound having an endothelin receptor antagonistic action used in the present invention, W
O93 / 08799, WO93 / 13218, WO93
/ 21219, EP-A-555,537, JP-A-5-
178890 and 5-279390, EP-A-5.
58,258, WO93 / 23404, EP-A-56.
9, 193, WO93 / 17701 and Bioorganic & Medicianl Chemistry Letters 1
0, pages 2099-2104 (1993) and the like. Among them, EP-A-552
489, EP-A-528, 312, EP-A-49
9,266, WO91 / 13089, EP-A-43.
6,189, EP-A-457,195, EP-A-51
0,526, WO92 / 12991, EP-A-526,
The compounds described in 708 and WO93 / 08799 are preferred, and particularly preferred are the compounds described in EP-A-528,312. The compounds will be described below.

[EP-A-0,528,312] Formula [A]

[0103]

[Chemical 43]

[Wherein X and Y are α-amino acid residues, A is a D-acidic-α-amino acid residue, and B is a neutral-amino acid residue.
an α-amino acid residue, C an L-α-amino acid residue, and D an aromatic ring group-containing D-α-amino acid residue] or a salt thereof. In the above compound [A], A is a C _3-5 -D-acidic-α-amino acid residue, preferably C
_A compound which is a _3-5 -D-α-aminodicarboxylic acid residue, a C _3-11 -L-α-amino acid residue in which X may be substituted, preferably a heterocyclic group which may have a substituent A compound which is a C _3-5 -L-α-aminodicarboxylic acid residue which may be substituted with a ring group, Y is an L-acidic α-amino acid residue, preferably C _3-5 -L-α-
A compound which is an aminodicarboxylic acid residue, B may be substituted with a C _2-6 -D-neutral-α-amino acid residue which may have a heterocyclic group, preferably a sulfur-containing heterocyclic group A compound which is a good C _2-6 -D-α-aminomonocarboxylic acid residue, C is an L-neutral-α-amino acid residue, preferably C _5-6 -L-α
-A compound which is an aminomonocarboxylic acid residue, D has an optionally substituted aromatic heterocyclic group, D-neutral-α-amino acid residue, preferably a nitrogen-containing aromatic heterocyclic group And compounds that are D-neutral-α-amino acid residues.

Preferred examples of the substituted C _3-11 -L-α-amino acid in the _optionally substituted C _3-11 -L-α-amino acid residue include, for example, substituted functional groups (eg, , C _3-11 -L-α-amino acid having a hydroxyl group, a mercapto group, an amino group, an imino group, a carboxyl group and the like). Examples of the substituted functional group include the above-mentioned substituted hydroxyl group, thiol group, amino group (or imino group), and carboxyl group. As the heterocyclic group which may have a substituent or the heterocyclic group, as the heterocyclic group, for example, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like in addition to a carbon atom. Containing 5 or 6 membered ring groups (eg 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl , 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5imidazolyl,
3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4
-Oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5- (1,2,4-thiadiazolyl),
1,3,4 thiadiazolyl, 4- or 5- (1,2,
3-thiadiazolyl,) 1,2,5-thiadiazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, 2-, 4- or 5-pyrimidinyl, thiomorpholinyl, morpholinyl, oxoimidazolinyl, dioxotriazinyl, pyrrolidinyl , Piperidinyl, pyranyl, thiopyranyl,
1,4-oxazinyl, 1,4-thiazinyl, 1,3-
Thiadinyl, piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl etc.) and the like. Examples of the substituent include an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), a cycloalkenyl group having 5 to 7 carbon atoms (eg, Cyclopentenyl, cyclohexenyl group, etc.), aralkyl group having 7 to 11 carbon atoms (eg, benzyl, α-methylbenzyl, phenethyl group, etc.), 6 carbon atoms
To 10 aryl groups (eg, phenyl, naphthyl, anthracenyl, etc.), alkoxy groups having 1 to 6 carbon atoms (eg, methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert. -
Butoxy group), alkanoyl group having 1 to 6 carbon atoms (eg, formyl, acetyl, propionyl, n-butyryl, is
o-butyryl group etc.) and the like. The number of substitutions is 1 to 5, preferably 1 to 3. Further, these substituents are, for example, halogen atoms (eg, fluorine, chlorine,
Bromine, iodine), mono-, di- or tri-halogeno-C
_1-4 alkyl group (eg, chloromethyl, dichloromethyl, trifluoromethyl, trifluoroethyl, etc.), carbon number 1
Or 1 to 3 alkoxy groups (eg, methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy groups, etc.) and the like. Examples of the sulfur-containing heterocyclic group include a 5- or 6-membered ring group containing 1 to 2 sulfur atoms in addition to carbon atoms (eg, 2- or 3-thienyl, thiomorpholinin, dithianyl, thiopyranyl, etc.).

Examples of the acyl group in the case of being acylated include an acyl group derived from an organic carboxylic acid. Specific preferred examples of the acyl group include:
For example, formyl group, C _1-6 alkyl-carbonyl group (eg, acetyl, ethylcarbonyl, hexylcarbonyl, etc.), C _6-10 aryl-carbonyl group (eg, phenylcarbonyl, naphthylcarbonyl, etc.), C _7-11 aralkyl- Carbonyl (eg, benzylcarbonyl etc.) can be mentioned. As the aromatic heterocyclic group, for example, 1 to 4 heteroatoms, which may be condensed with a benzene ring, selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like in addition to the carbon atom.
5 to 6-membered aromatic heterocyclic group containing 1 (eg, 2 or 3-)
Thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4 -Or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3-or 5- (1,2,4-oxadiazolyl) , 1, 3,
4-oxadiazolyl, 3- or 5- (1,2,4-
Thiadiazolyl), 1,3,4-thiadiazolyl, 4-
Or 5- (1,2,3-thiadiazolyl), 1,2,
5-thiadiazolyl, 1,2,3-triazolyl, 1,
2,4-triazolyl, 1H- or 2H-tetrazolyl, 2-, 4- or 5-pyrimidinyl, 2- or 3
-Indolyl, 1-, 2- or 3-indolizinyl,
2- or 3-quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinolinyl, 2-benzimidazolyl and the like). As the nitrogen-containing aromatic heterocyclic group, for example, a 5- to 6-membered aromatic heterocyclic group containing 1 to 3 nitrogen atoms in addition to the carbon atom which may be condensed with the benzene ring (eg, 2- or 3- Pyrrolyl, 2-, 3- or 4-pyridyl, 3-, 4- or 5-pyrazolyl, 2
-, 4- or 5-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H
-Tetrazolyl, 2-, 4- or 5-pyrimidinyl,
2- or 3-indolyl, 1-, 2- or 3-indolidinyl, 2- or 3-quinolyl, phthalazinyl,
Quinoxalinyl, quinazolinyl, cinolinyl, 2-benzimidazolyl and the like).

Specifically, EP-A-0,528,312
The cyclic peptide or salt thereof shown in the Example is used in Cyclo [-D-Asp-Asn (CH2CH2-Ind) -Asp-D-Leu-Leu-D-Trp-]: Example 12 Cyclo [- D-Asp-Trp-Asp-D-Leu-Leu-D-Trp (For)-]: Example 42 Cyclo [-D-Asp-Trp-Asp-D-Thg (3) -Leu-D-Trp-] ]: Example 49 Cyclo [-D-Asp-Trp-Asp-D-γMeLeu-Leu-D-Trp-]: Example 54 Cyclo [-D-Asp-Trp-Asp-D-Thg (2) -Leu -D-Trp-]: example 55 Cyclo _{[-D-Asp-Gln (CH 2} Ph) -Asp-D-Leu-Leu-D-Trp- ]: example 62 Cyclo [-D-Asp-Asp ( R1) -Asp-D-Leu-Leu-D-Trp-]: Example 70 Cyclo [-D-Asp-Asp (R2) -Asp-D-Leu-Leu-D-Trp-]: Example 71 Cyclo [-D-Asp-Orn (COCH ₂ Ph) -Asp-D-Leu-Leu-D-Trp-]: Example 80 Cyclo [-D-Asp-Orn (COCH ₂ -Ind) -Asp-D-Leu -Leu-D-Trp-]: Example 82 Cyclo [-D-Asp-Hyp (Bzl) -Asp-D-Thg (2) -Leu-D-Trp-]: Example 88 Cyclo [-D-Asp -Gln (Bzl) -Asp-D- Thg (2) -Leu-D-Trp- ]: example 89 Cyclo _{[-D-Asp-Asn (CH 2} CH 2 -Ind) -Asp-D-Thg (2 ) -Leu-D-Trp-]: Example 0 Cyclo [-D-Asp-Asp (R1) -Asp-D-Thg (2) -Leu-D-Trp-]: Example 96 Cyclo [-D-Asp-Asp (R7) -Asp-D-Thg (2) -Leu-D-Trp-]: Example 136 Cyclo [-D-Asp-Asp (R10) -Asp-D-Thg (2) -Leu-D-Trp-]: Example 139 Cyclo [- D-Asp-Asp (R12) -Asp-D-Thg (2) -Leu-D-Trp-]: Example 141 Cyclo [-D-Asp-Asp (R13) -Asp-D-Thg (2)- Leu-D-Trp-]: Example 142 Cyclo [-D-Cta-Asp (R1) -Asp-D-Thg (2) -Leu-D-Trp-]: Example 146 Cyclo [-D-Cta-] Asp (R7) -Asp-D-Thg (2) -Leu-D-Trp-]: Example 147 Cyclo [-D-Cta-Asp (R10) -Asp-D-Thg (2) -Leu-D- Trp-]: Example 150 Cyclo [-D-Cta-Asp (R12) -Asp-D-Thg (2) -Leu-D-Trp-]: Example 152 Cyclo [-D-Cta-Asp (R13) -Asp-D-Thg (2) -Leu-D-Trp-]: Example 153 Cyclo [-D-Asp-Asp (R1) -Asp-D-Cpg-Leu-D-Trp-]: Example 157 Cyclo [-D-Cta-Asp (R1) -Asp-D-Cpg-Leu-D-Trp-]: Example 168 is preferred.

The above formula [A] indicates that a ring is formed as a whole molecule by the presence of 6 amide bonds including A to D, and cyclo [-A-X-Y-B- It may be expressed as C-D-]. In the above formula [A], the base amino acid of the α-amino acid residue represented by X or Y may be any amino acid as long as it is an α-amino acid.
Alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, 2-aminomalonic acid, 2-aminoadipic acid, glycine, histidine, isoleucine, leucine, lysine, ornithine,
2,4-diaminobutyric acid, methionine, phenylalanine,
Proline, 4-hydroxyproline, thioproline, azetidine-2-carboxylic acid, pipecolic acid (piperidine-2
-Carboxylic acid), indoline-2-carboxylic acid, tetrahydroisoquinoline-3-carboxylic acid, serine, threonine,
Tryptophan, 5-methyltryptophan, tyrosine, valine, alloisoleucine, norvaline, norleucine, tertiary leucine, gamma methylleucine,
Phenylglycine, 2-aminobutyric acid, cysteic acid, homocysteic acid, 3- (1-naphthyl) alanine, 3-
(2-naphthyl) alanine, 2- (2-thienyl) glycine, 2- (3-thienyl) glycine, 3- (3-benzothienyl) alanine, 3- (4-biphenyl) alanine,
Pentamethylphenylalanine, 1-aminocyclopropane-1-carboxylic acid, 1-aminocyclobutane-1-carboxylic acid, 1-aminocyclopentane-1-carboxylic acid, 1-
Examples thereof include aminocyclohexane-1-carboxylic acid and 1-aminocycloheptane-1-carboxylic acid. When these α-amino acids have functional groups (eg, hydroxyl group, thiol group, amino group, imino group, carboxyl group, etc.), these functional groups may be substituted.

Examples of the substituted hydroxyl group include C _1-6 fatty acid ester (for example, formic acid ester, acetic acid ester, propionic acid ester, etc.), C _4-9 alicyclic carboxylic acid ester (for example, cyclopentane carboxylic acid ester,
Cyclohexanecarboxylic acid ester, etc.), C _7-15 arylcarboxylic acid ester (eg, benzoic acid ester, 4-methylbenzoic acid ester, etc.), C _8-16 aralkylcarboxylic acid ester (eg, phenylacetic acid ester, 2-phenylpropione) Acid ester, 3-phenylpropionic acid ester, diphenylacetic acid ester, etc.), aromatic heterocycle-alkylcarboxylic acid ester (eg, indol-2-yl acetic acid ester, indole
Ester such as (3-ylacetic acid ester), C _1-6
Alkyl ether (eg, methyl ether, ethyl ether, n-propyl ether, tertiary butyl ether, etc.), C _3-8 cycloalkyl ether (eg, cyclopentyl ether, cyclohexyl ether, etc.), C _6-12 aryl ether (eg, phenyl) Ether, 4-methylphenyl ether, etc.), C
_7-15 aralkyl ether (for example, benzyl ether, phenethyl ether, diphenyl methyl ether, etc.) and the like. Examples of the α-amino acid substituted with a hydroxyl group include O-acetylserine, O-acetylthreonine, 4-acetoxyproline, O-benzoylserine, O-benzoylthreonine,
4-benzoyloxyproline, O-phenylacetylserine, O-phenylacetylthreonine, 4-phenylacetoxyproline, O-ethylserine, O-ethylthreonine, 4-ethoxyproline, O-cyclohexylserine, O-cyclohexylthreonine, 4- Cyclohexyloxyproline, O-phenylserine, O-phenylthreonine, 4-phenoxyproline, O-benzylserine,
O-benzyl threonine, 4-benzyloxyproline,
Examples thereof include O-diphenylmethylserine, O-diphenylmethylthreonine, 4-diphenylmethoxyproline and the like. Examples of the substituted thiol group include C _1-6 fatty acid thiol ester (eg, formic acid thiol ester, acetic acid thiol ester, propionic acid thiol ester, etc.), C _4-9 alicyclic carboxylic acid thiol ester (eg, cyclopentanecarboxylic acid thiol) Ester, cyclohexanecarboxylic acid thiol ester, etc.), C
_7-15 arylcarboxylic acid thiol ester (for example,
Benzoic acid thiol ester, 4-methylbenzoic acid thiol ester, etc., C _8-16 aralkylcarboxylic acid thiol ester (eg, phenylacetic acid thiol ester, 2-phenylpropionic acid thiol ester, 3-phenylpropionic acid thiol ester, diphenylacetic acid Thiol ester such as thiol ester), C
_1-6 alkyl thioether (eg, methyl thioether, ethyl thioether, n-propyl thioether, tertiary butyl thioether, etc.), C _3-8 cycloalkyl thioether (eg, cyclopentyl thioether, cyclohexyl thioether, etc.), C
_6-12 aryl thioether (eg, phenyl thioether, 4-methylphenyl thioether, etc.), C
_7-15 aralkyl thioethers (eg, benzyl thioether, phenethyl thioether, diphenylmethyl thioether, etc.) and the like. Examples of the α-amino acid substituted with a thiol group include S-acetyl cysteine, S-benzoyl cysteine, S-phenyl acetyl cysteine, S-ethyl cysteine, S-cyclohexyl cysteine, S-phenyl cysteine and S-benzyl cysteine. Can be given.

The substituted amino group (or imino group) is C _1-6 alkylamino (or imino) (for example,
N-methylamino (or imino), N-ethylamino (or imino), N-tert-butylamino (or imino) and the like), C _3-8 cycloalkylamino (or imino) (for example, N-cyclopentylamino ( Or imino), N-cyclohexylamino (or imino), etc.),
C _6-12 arylamino (or imino) (eg N-
Phenylamino (or imino), N- {4-methylphenyl} amino (or imino), etc., C _7-15 aralkylamino (or imino) (eg, N-benzylamino (or imino), N-phenethylamino ( Or imino), N
-{2-chlorobenzyl} amino (or imino), N- {3-
Chlorobenzyl} amino (or imino), N- {4-chlorobenzyl} amino (or imino), N- {2-methylbenzyl} amino (or imino), N- {3-methylbenzyl} amino (or imino) , N- {4-methylbenzyl} amino
(Or imino), N- {2-methoxybenzyl} amino (or imino), N- {3-methoxybenzyl} amino (or imino), N- {4-methoxybenzyl} amino (or imino), etc.), aromatic Group heterocycles-C _1-6 alkylamino (or imino) (eg 2-furylmethylamino (or imino), 3-furylmethylamino (or imino), 2-thienylmethylamino (or imino), 3-thienyl) Methylamino (or imino), indol-2-ylmethylamino (or imino), indol-3-ylmethylamino
(Or imino)), etc., a substituted amino form (or imino form), C _1-6 aliphatic acylamide (or imide) (eg, formamide (or imide), acetamide (or imide), propionamide (or imide), etc.) ,
C _4-9 alicyclic acylamide (or imide) (for example,
Cyclopentanecarbonylamide (or imide), cyclohexanecarbonylamide or imide), etc., C
_{7-15 arylacyl} amides (eg benzamide
(Or imide), 4-methylbenzamide (or imide), etc., C _8-16 aralkylacylamide (eg, phenylacetamide (or imide), 2-phenylpropionamide (or imide), 3-phenylpropionamide (or Imide), diphenylacetamide
(Or imide), 1-naphthylacetamide (or imide), 2-naphthylacetamide (or imide), etc.),
Aromatic heterocycle-carbonyl amide (or imide) (eg, indol-2-ylcarbonylamide (or imide), indol-3-ylcarbonylamide (or imide), etc.), aromatic heterocycle-alkylcarbonylamide
(Or imide) (eg, indol-2-ylacetamide (or imide), indol-3-ylacetamide (or imide), etc.), sulfonylamide (or imide) (eg, benzenesulfonylamide (or imide), paratoluene) Substituted amides such as sulfonylamide (or imide), 4-methoxy-2,3,6-trimethylbenzenesulfonylamide (or imide), etc.
(Or imide form) and the like. Examples of the α-amino acid substituted with an amino (or imino) group include N-methylglycine (sarcosine), N-ethylglycine, N-methylleucine, N-ethylleucine, N-methylphenylalanine and N-ethylphenylalanine. , N
(α) -methyltryptophan, N (α) -ethyltryptophan, N-cyclopentylglycine, N-cyclohexylglycine, N-phenylglycine, N-phenylleucine, N-benzylglycine, N-benzylleucine, N
(π) -Benzylhistidine, N (τ) -benzylhistidine, N (π) -phenacylhistidine, N (π) -benzyloxymethylhistidine, N ^g -benzenesulfonylarginine, N ^g -paratoluenesulfonylarginine, N ^g-
(4-Methoxy-2,3,6-trimethylbenzenesulfonyl) arginine, N (ε) -benzenesulfonyllysine, N
(epsilon) - p-toluenesulfonyl lysine, N (ε) - (4- methoxy-2,3,6) lysine, N ⁱⁿ - methyl tryptophan, N ⁱⁿ - ethyl tryptophan, N ⁱⁿ - formyl tryptophan, N ⁱⁿ -acetyltryptophan, N (ε) -benzyl lysine, N (ε)-(2-
Furylmethyl) lysine, N (ε)-(2-thienylmethyl) lysine, N (ε)-(indol-3-ylmethyl) lysine, N
(ε) -Phenylacetyllysine, N (ε)-({2-furyl} acetyl) lysine, N (ε)-({2-thienyl} acetyl) lysine, N (ε)-({Indol-3-yl } Acetyl) lysine,
N (ε) -benzoyl lysine, N (ε)-(3-phenylpropionyl) lysine, N (δ) -benzylornithine, N (δ)-
(2-Furylmethyl) ornithine, N (δ)-(2-thienylmethyl) ornithine, N (δ)-(indol-3-ylmethyl)
Ornithine, N (δ) -benzoylornithine, N (δ) -phenylacetylornithine, N (δ)-(3-phenylpropionyl) ornithine, N (δ)-({2-methylphenyl} acetyl) ornithine, N ( δ)-({3-methylphenyl} acetyl) ornithine, N (δ)-({4-methylphenyl} acetyl) ornithine, N (δ)-({2-chlorophenyl} acetyl) ornithine, N (δ)- ({3-Chlorophenyl} acetyl) ornithine, N (δ)-({4-chlorophenyl} acetyl) ornithine, N (δ)-({2-methoxyphenyl} acetyl) ornithine, N (δ)-({3- Methoxyphenyl} acetyl) ornithine, N (δ)-({4-methoxyphenyl} acetyl) ornithine, N (δ)-(4-biphenylacetyl) ornithine, N (γ) -benzyl-2,4-diaminobutyric acid, N (γ)
-(2-furylmethyl) -2,4-diaminobutyric acid, N (γ)-(2-
Thienylmethyl) -2,4-diaminobutyric acid, N (γ)-(indol-3-ylmethyl) -2,4-diaminobutyric acid, N (γ) -benzoyl-2,4-diaminobutyric acid, N (γ)- Phenylacetyl-2,4-diaminobutyric acid, N (γ)-(3-phenylpropionyl) -2,4-diaminobutyric acid, N (γ)-(2-furylacetyl) -2,4-diaminobutyric acid, N ( Examples include γ)-(2-thienylacetyl) -2,4-diaminobutyric acid and N (γ)-({indol-3-yl} acetyl) -2,4-diaminobutyric acid.

Amide as the substituted carboxyl group
(-CONH ₂ ), N-C _1-6 alkylamide (for example, N-methylamide, N-ethylamide, N- {n-propyl} amide, N-tert-butylamide, etc.), N-C _3-8 cyclo Alkylamide (eg, N-cyclopentylamide, N-cyclohexylamide, etc.), N—C _6-12 arylamide (eg, N-phenylamide, N- {4-methylphenyl} amide, etc.), N—C _{7- 15} Aralkylamides (eg N-benzylamide, N-phenethylamide, N- {1,2-diphenylethyl} amide, N- {aromatic heterocycle-C _1-6 alkyl} amide (eg N- [2 -{Indol-2-yl} ethyl] amide, N- [2- {indole
-3-yl} ethyl] amide), piperidine amide, piperazine amide, N ⁴ -C _1-6 alkyl piperazine amide (eg, N ⁴ -methyl piperazine amide, N ⁴ -ethyl piperazine amide, etc.), N ⁴ -C _3-8 cycloalkyl piperazine amides (e.g., N ⁴ - cyclopentyl piperazine amide, N ⁴ - cyclohexyl piperazine amide), N ⁴ -C _6-12 aryl piperazine amides (e.g., N ⁴ - phenylpiperazine amide, N ⁴ - { a 4-methylphenyl} piperazine amide), N ⁴ -C _7-15 aralkyl piperazine amides (e.g., N ⁴ - benzylpiperazine amide, N ⁴ - phenethyl piperazine amide, N ⁴ - {1,
2-diphenylethyl} piperazine amide, N ⁴ - {aromatic heterocycle -C _1-6 alkyl} piperazine amides (e.g.,
N ⁴ - [2- {indol-2-yl} ethyl] piperazine amide, N ⁴ -, etc. [2- {indol-3-yl} ethyl] piperazine amide), N ⁴ -C _1-6 aliphatic acyl piperazine amide (For example, N ⁴ -acetyl piperazine amide, N ⁴ -propionyl piperazine amide, etc.), N ⁴ -C _4-9 alicyclic acyl piperazine amide (eg, N ⁴ -cyclopentane carbonyl piperazine amide, N ⁴ -cyclohexane carbonyl piperazine amide, etc.) ), N ⁴ -C _7-15 aryl acyl piperazine amides (e.g., N ⁴ - benzoyl piperazine amide, N ⁴ - {4- methylbenzoyl} piperazine amides such), N ⁴ -C _8-16 aralkyl acyl piperazine amide (e.g. , N ⁴ - phenylacetyl piperazine amide, N ⁴ - {2- phenylpropionic} piperazine amide, N ⁴ - {3- Fenirupu Pioniru} piperazine amide, N ⁴ - diphenylacetyl piperazine amide, N ⁴ -
{1-naphthyl acetyl} piperazine amide, N ⁴ - such as {2- naphthylacetyl} piperazine amide), N ⁴ - {aromatic heterocyclic - carbonyl} piperazine amides (e.g., N ⁴ -
{Indol-2-ylcarbonyl} piperazine amide, N
⁴ - like {indol-3-yl carbonyl} piperazine amide), N ⁴ - {aromatic heterocycle - alkyl carbonyl} piperazine amides (e.g., N ⁴ - {indol-2-ylacetyl} piperazine amide, N ⁴ - {indol -3-yl acetyl} piperazine amide etc.), C _1-6 alkyl ester (eg methyl ester, ester ester, n-propyl ester etc.), C _3-8 cycloalkyl ester (eg cyclopentyl ester,
And cyclohexyl ester) and C _7-15 aralkyl ester (eg, benzyl ester, phenethyl ester, 1-phenylethyl ester, diphenylmethyl ester, etc.) and the like. Among the above amides, amides with α-amino acids and oligopeptides (for example, dipeptides, tripeptides,
Amides with tetrapeptides, etc.) are also included. The α- amino acid in which a carboxyl group is substituted, for example, N ⁴ - methyl aspartate, N ⁴ - phenyl asparagine, N4-benzyl aspartate, N ⁴ - phenethyl asparagine, N ⁴ - (2- {indol-3-yl} ethyl) asparagine, N ⁵ - methyl glutamine, N ⁵ - phenyl glutamine, N ⁵ - benzyl glutamine, N ⁵ - phenethyl glutamine, N ⁵ - (2- {indol-3-yl} ethyl) glutamine, aspartic acid β- methyl ester, aspartic acid β- cyclopropyl ester, aspartic acid β- benzyl ester, aspartic acid β- phenethyl ester, aspartic acid beta-N4-phenylpiperazine amide, aspartic acid β-N ⁴ - (2- methylphenyl) piperazine amide, Aspartic acid β-N4- (3-methylphenyl) piperazine amide, asparagi Phosphate β-N ⁴ - (4-
Methylphenyl) piperazine amide, aspartic acid β
-N ⁴ - (2-methoxyphenyl) piperazine amide, beta-N4-aspartic acid (3-methoxyphenyl) piperazine amide, aspartic acid β-N ⁴ - (4- methoxyphenyl)
Piperazine amide, aspartic acid β-N ⁴ - (2- chlorophenyl) piperazine amide, aspartic acid β-N ⁴ -
(3-chlorophenyl) piperazine amide, aspartic acid β-N ⁴ - (4- chlorophenyl) piperazine amide, aspartic acid β-N ⁴ - (4- nitrophenyl) piperazine amide, aspartic acid β-N ⁴ - (4- fluoro phenyl) piperazine amide, aspartic acid β-N ⁴ - (3- trifluoromethylphenyl) piperazine amide, aspartic acid β-N ⁴ - (2,3- dimethylphenyl) piperazine amide, aspartic acid β-N ⁴ - (2 - pyridyl) piperazine amide, aspartic acid β-N ⁴ - (2- pyrimidyl)
Piperazine amide, glutamic acid γ-methyl ester,
Examples thereof include glutamic acid γ-cyclopropyl ester, glutamic acid γ-benzyl ester, and glutamic acid γ-phenethyl ester.

In the above formula [A], the α-amino acid which is the mother of the α-amino acid residue represented by X or Y is D-form, L-form
Either the body or the DL body may be used, but the L body is more preferable for both X and Y. In the above formula [A], D- represented by A-
As the base amino acid for acidic-α-amino acid residues,
For example, an amino acid having an acidic group such as a carboxyl group, a sulfonyl group or a tetrazolyl group in its side chain can be mentioned. Specific examples thereof include D-glutamic acid, D-aspartic acid, D-cysteic acid, D-homocysteic acid,
D-β- (5-tetrazolyl) alanine, D-2-amino-4- (5
-Tetrazolyl) butyric acid and the like can be mentioned, but D-glutamic acid, D-aspartic acid and D-cysteic acid are particularly preferable. In the above formula [A], as the base amino acid of the neutral-α-amino acid residue represented by B, for example, alanine, valine, norvaline, leucine, isoleucine, alloisoleucine, norleucine, tertiary leucine, gamma Methylleucine, phenylglycine, phenylalanine, 3- (1-naphthyl) alanine, 3-
(2-naphthyl) alanine, proline, 4-hydroxyproline, azetidine-2-carboxylic acid, pipecolic acid (piperidine-2-carboxylic acid), 3- (2-thienyl) alanine, 2- (2-thienyl) glycine, 2- (3-thienyl) glycine, 1-aminocyclopropane-1-carboxylic acid, 1-aminocyclobutane-1-carboxylic acid, 1-aminocyclopentane-1-carboxylic acid, 1-aminocyclohexane-1-carboxylic acid Examples thereof include α-amino acids such as 1-aminocycloheptane-1-carboxylic acid, 2-cyclopentylglycine and 2-cyclohexylglycine. When the neutral α-amino acid has L-form and D-form, the D-form is preferred. Especially, D-leucine, D-alloisoleucine, D-tert-leucine, D-gammamethylleucine, D-phenylglycine, D-3- (2-thienyl) alanine, D-2- (2-thienyl) glycine, D -2- (3-thienyl) glycine and D-2- (2-cyclopentyl) glycine are more preferable. The α-imino groups of these neutral-α-amino acids are C _1-6 alkyl groups (eg methyl, ethyl,
n-propyl, tert-butyl, etc.). Examples of such α-amino acids include N-methylleucine, N-methylalloyisoleucine, N-methyltertiary leucine, N-methylgammamethylleucine, N-methylphenylglycine, and the like, and these D-forms are also included. Is preferred.

In the above formula [A], L-α represented by C
-Examples of the amino acid that is the base of the amino acid residue include, for example, glycine, L-alanine, L-valine, L-norvaline,
L-leucine, L-isoleucine, L-tertiary leucine, L-norleucine, L-methionine, L-2-aminobutyric acid, L-serine, L-threonine, L-phenylalanine, L-
Aspartic acid, L-glutamic acid, L-asparagine, L-
Commonly known L-α-amino acids such as glutamine, L-lysine, L-tryptophan, L-arginine, L-tyrosine, and L-proline are listed, and particularly L-leucine, L-norleucine, and L-tryptophan. Is preferred. these
The α-imino group of the L-α-amino acid may be substituted with a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, tert-butyl etc.). Such L-α
-Examples of amino acids include L-N-methylleucine,
Examples thereof include L-N-methylnorleucine and L-N (α) -methyltryptophan. In the above formula [A], examples of the amino acid that is the base of the D-α-amino acid residue having an aromatic ring group represented by D include D-α-amino acids having an aromatic ring group in the side chain. . Specific examples thereof include D-tryptophan, D-5-methyltryptophan, D
-Phenylalanine, D-tyrosine, D-3- (1-naphthyl) alanine, D-3- (2-naphthyl) alanine, D-3-
Examples thereof include (3-benzothienyl) alanine, D-3- (4-biphenyl) alanine and D-pentamethylphenylalanine, with D-tryptophan and D-5-methyltryptophan being preferred. Among them, D-tryptophan is more preferable. Α-of D-α-amino acids having these aromatic rings
The imino group may be substituted with a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, tert-butyl, etc.), and the imino group of the indole ring of D-tryptophan is C _1-6 alkyl. (Eg, methyl, ethyl, n-propyl, tert-butyl), C _3-8 cycloalkyl (eg, cyclopentyl, cyclohexyl, etc.), C _6-12 aryl (eg, phenyl, 4-
Methylphenyl, etc.), C _7-15 aralkyl (eg,
Benzyl, phenethyl, etc.) hydrocarbon groups and C _1-6
Aliphatic acyl (eg formyl, acetyl, propionyl etc.), C _4-9 alicyclic acyl (eg cyclopentanecarbonyl, cyclohexanecarbonyl etc.), C _{7-15 arylacyl} (eg benzoyl,
4-methylbenzoyl etc.), C _8-16 aralkylacyl (eg phenylacetyl, 2-phenylpropionyl, 3-phenylpropionyl, diphenylacetyl etc.), C _1-6 alkoxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl etc.) It may be substituted with an acyl group such as. Examples of such α-amino acids include D-N (α) -methyltryptophan, D-N-methylphenylalanine, D-N-methyltyrosine, D-N ⁱⁿ -methyltryptophan and D-N ⁱⁿ -ethyltryptophan. , D-N ⁱⁿ -formyl tryptophan, D-N ^in-
Examples include acetyltryptophan. Above all
D-N ⁱⁿ - methyl tryptophan, D-N ⁱⁿ - formyl tryptophan, D-N ⁱⁿ - acetyl tryptophan it is more preferred. The salt of the cyclic peptide [A] of the present invention includes a metal salt (eg, sodium salt, potassium salt, calcium salt, magnesium salt, etc.), a salt with a base or a basic compound (eg, ammonium salt, arginine salt, etc.). , Inorganic acid addition salts (eg, hydrochloride, sulfate, phosphate, etc.), organic acid salts (eg, acetate, propionate, citrate, tartrate, malate, oxalate, etc.) can give.

[EP-A-552,489] Formula [B]

[0115]

[Chemical 44]

[In the formula, R ₁ is a fat-soluble group, R ₂ and R ₅ are each a hydrogen atom or a lower alkyl group, and R ₃ is an aliphatic group which may contain an oxygen atom or a sulfur atom, R ₄ is an optionally substituted heterocycle-lower alkyl group, R ₆ is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted aromatic ring group, and X is an aromatic ring. Group, n is 0 or an integer of 1 or more, and m is an integer of 2 or more. ] The peptide or its salt represented by these.

Specifically, the peptides or salts thereof shown in the examples in Japanese Patent Application No. 4-344252 are used, particularly Hexamethyleneimino-CO-Leu- (D) Trp- (D).
Ala-β Ala-Tyr- (D) Phe-OH or its salt, Hexamethylene
imino-CO-Leu- (D) Trp- (D) Ala-βAla-Tyr (I)-(D) Phe-OH
Or its salt, Hexamethyleneimino-CO-Leu- (D) Trp- (D)
Ala-βAla-Trp-NH-Ind-OH or a salt thereof is suitable.

In the above formula [B], R ₁ represents a fat-soluble group. The lipophilic group may be any group as long as it is a group that enhances the lipophilicity of the compound by binding the group. As the fat-soluble group, for example, an alkyl group, a cycloalkyl group, an alkoxy group, an aromatic ring group, a substituted amino group and the like are used, and these groups may be further substituted.

The alkyl group as R _{1 has 1 to} 10 carbon atoms.
Linear or branched alkyl groups are preferred, for example methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isoamyl, tert-amyl,
Neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like are used. Particularly, a lower alkyl group having 1 to 6 carbon atoms (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,
n-pentyl, isoamyl, tert-amyl, neopentyl, n-hexyl, etc.) are preferred. These alkyl groups may be substituted, and as the substituents, C _3-8 cycloalkyl (cyclopentyl, cyclohexyl, etc.), halogen (fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkoxy (methoxy, ethoxy). , N-propoxy, isopropoxy, n-butoxy, tert-
Butoxy), C _1-6 alkylthio (methylthio, ethylthio, n-propylthio, isopropylthio, n-
Butylthio, tert-butylthio, etc.), C _1-6 alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, etc.), aromatic ring group (eg, phenyl,
Fluorophenyl, chlorophenyl, bromophenyl,
Halogen atom such as hydroxyphenyl, methoxyphenyl, methylphenyl, 1-naphthyl, 2-naphthyl,
C _6-12 aromatic hydrocarbon group which may be substituted with hydroxy group, C _1-3 alkoxy group, C _1-3 alkyl group or the like, furyl, thienyl, thiazolyl, indolyl, pyridyl,
A 5- to 10-membered aromatic heterocyclic group containing 1 to 4 heteroatoms such as O, S and N such as pyranyl, imidazolyl, pyrimidyl and quinolyl) is used. The number of substituents on these alkyl groups is preferably 1 to 3.

The cycloalkyl group as R ₁ has 3 carbon atoms.
A cycloalkyl group of -10 is preferable, and for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, bornyl, norbornyl and the like can be used. These cycloalkyl groups may be substituted, and as the substituents, C _1-6 alkyl (methyl, ethyl, n-propyl, n-butyl etc.), halogen (fluorine, chlorine, bromine, iodine etc.), C _1-6 alkoxy (methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, etc.), C _1-6 alkylthio (methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio) Etc.), C _1-6 alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,
(tert-butoxycarbonyl etc.) and the like are used. As the number of substituents of these cycloalkyl groups,
1 to 3 is preferred. In addition, the above cycloalkyl group is condensed with another ring (for example, a benzene ring) (for example, indan-1-yl, indan-2-yl, 1,2,3,4-tetrahydronaphthalene-1-). Yl, 1,2,3,4-tetrahydronaphthalen-2-yl, etc.) are also included.

The alkoxy group as R ₁ has 1-8 carbon atoms.
Linear or branched alkoxy groups are preferred, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isoamyloxy, tert. -Amyloxy, neopentyloxy, n-hexyloxy, n-heptyloxy, n-
Octyloxy and the like are used. These alkoxy groups may be substituted, and as the substituent, C _3-8 cycloalkyl (cyclopentyl, cyclohexyl, etc.),
C _1-6 alkoxy (methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, etc.), C _1-6 alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, etc.) Are used. The number of substituents of these alkoxy groups is 1
To 3 are preferred. The alkyl group or alkoxy group as R ₁ is preferably branched.

The aromatic ring group as R ₁ may be either an aromatic hydrocarbon group or an aromatic heterocyclic group. As the aromatic hydrocarbon group, those having 6 to 15 carbon atoms such as phenyl and α-naphthyl are used. These aromatic hydrocarbon groups include, for example, halogen atom (eg, fluoro, chloro, bromo), hydroxy group, C _1-6 alkyl group (eg, methyl, ethyl), C _1-6 alkoxy group (eg,
Methoxy, ethoxy), carboxyl group, C _1-6 alkylcarbonyl (eg, formyl, acetyl), C _1-6 alkoxycarbonyl (eg, acetoxy) and the like, which may have 1 to 3 substituents. Good. Examples of the optionally substituted aromatic hydrocarbon group include phenyl, 4-fluorophenyl, 4-chlorophenyl and 4
-Bromophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-methylphenyl, 1-naphthyl, 2
-Naphthyl and the like are often used. The aromatic heterocyclic group is, for example, a 5-6 membered one containing 1-4 heterocyclic ring atoms such as O, S, N (for example, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl). , Thiazol-4-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-
Pyranyl etc.) or those condensed with other aromatic rings (eg benzene ring etc.) (eg indol-3-yl, N-methylindol-3-yl, 2-quinolyl, quinoxalin-2-yl etc.) ) And the like are used. These aromatic heterocyclic groups may have, for example, 1 to 3 substituents similar to the substituents that the aromatic hydrocarbon group may have.

The substituted amino group as R ₁ is a mono-substituted amino group (R ₇ NH-) or a di-substituted amino group (R ₈ R ₉ N
-) Is preferable, and R ₇ , R ₈ and R ₉ are groups capable of imparting lipophilicity to the substituted amino group. As such R ₇ , R ₈ and R ₉ , an alkyl group having 4 or more carbon atoms, a cycloalkyl group having 5 or more carbon atoms, or an aromatic ring group is used. The alkyl group having 4 or more carbon atoms is more preferably an alkyl group having 4 to 10 carbon atoms, for example, n-butyl, isobutyl, sec-
Butyl, tert-butyl, n-pentyl, isoamyl, tert-amyl, neopentyl, n-hexyl,
N-heptyl, n-octyl, n-nonyl, n-decyl and the like are used. The cycloalkyl group having 5 or more carbon atoms is more preferably a cycloalkyl group having 5 to 10 carbon atoms, and examples thereof include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, bornyl and norbornyl. The aromatic ring group as R ₇ , R ₈ and R ₉ is, for example, a C _6-12 aromatic hydrocarbon such as phenyl, 1-naphthyl or 2-naphthyl, for example O,
5 to 10 containing 1-4 different ring atoms such as S and N
Membered aromatic heterocyclic groups (eg, furyl, thienyl, thiazolyl, pyridyl, pyranyl, etc.) or indolyl, quinolyl, quinoxalyl, etc., which are condensed with other aromatic rings (eg, benzene ring, etc.) are used. . Further, these alkyl group, cycloalkyl group and aromatic ring group may further have 1 to 3 substituents. Examples of the substituent of the alkyl group include C
_3-8 cycloalkyl (cyclopentyl, cyclohexyl, etc.), C _1-6 alkoxy (methoxy, ethoxy, n-
Propoxy, isopropoxy, n-butoxy, tert
-Butoxy), C _1-6 alkylthio (methylthio,
Ethylthio, n-propylthio, isopropylthio, n
-Butylthio, tert-butylthio, etc.), hydroxyl, carboxyl, C _1-6 alkylcarbonyl (formyl, acetyl) and the like are C _1-6 alkyl (methyl, ethyl, n) as the substituent on the carbon atom of the aromatic ring group. -Propyl, n-butyl etc.), C _1-6 alkoxy (methoxy, ethoxy, n-propoxy, n-butoxy etc.),
Hydroxyl, carboxy, C _1-6 alkylcarbonyl (formyl, acetyl) and the like, and C _1-6 alkyl (methyl, ethyl, n-propyl, n-butyl etc.) as a substituent on the carbon atom of the aromatic ring group. ), C _1-6 alkyl (methyl, ethyl, n-propyl, n-butyl, etc.) and the like are used. The di-substituted amino group (R ₈ R ₉ N-) has R
Those in which ₈ and R ₉ are combined to form a ring with the adjacent nitrogen atom are also included.

The ring formed by the combination of R ₈ and R ₉ is, for example, 5 to 13 which may contain 1 or 2 oxygen atoms, a hetero atom such as a sulfur atom, in addition to the nitrogen atom. A membered nitrogen-containing heterocycle or the like is used. Examples of the nitrogen-containing heterocycle include pyrrolinidino, piperidinino,
Hexamethyleneimino, heptamethyleneimino, oxazolidino, morpholino, thiazolidino, thiomorpholino, imidazolidino, piperazino, pyrrolino, 1,2-
Dihydropyridino, 1,4-dihydropyridino, 1,
2,3,6-tetrahydropyridino, 2-oxazolidonino, 2-thiazolidonino, imidazolino, pyrazolino, 1,4,5,6-tetrahydropyrimidino, 2,3
-Dihydro-1H-indolino, 1,2,3,4-tetrahydroquinolino, 2,3,4,5-tetrahydro-1
H-1-benzazepinino, 2,3-dihydro-1H-
Isoindolino, 1,2,3,4-tetrahydroisoquinolino, 2,3,4,5-tetrahydro-1H-2-benzazepinino, 2,3,4,5-tetrahydro-1H
-3-benzazepinino, 1,2,3,4,5,6-hexahydro-1-benzazocino, 1,2,3,4
5,6-hexahydro-2-benzazocino, 1,2,
3,4,5,6-hexahydro-3-benzazocino,
2,3,4,5,6,7-hexahydro-1H-1-benzazonino, 2,3,4,5,6,7-hexahydro-1H-2-benzazonino, 2,3,4,5,6,6 7
-Hexahydro-1H-3-benzazonino, 2,3
4,5,6,7-Hexahydro-1H-4-benzazonino, β-carbolino, phenoxazino, phenothinonyl, 3H-3-benzazepino, 3,4-dihydroquinolino, benzimidano, 1,4-benzodiazepino, 1
0,11-dihydro-5H-dibenz (b, f) azepin-5-yl and the like are used. Among them, hexamethyleneimino, 10,11-dihydro-5Hdibenz (b,
f) Azepin-5-yl, morpholino, piperidino, piperidino, piperazino and the like are preferable.

These heterocycles may have 1 to 3 substituents, for example, a C _1-6 alkyl group (eg,
Methyl, ethyl, n-propyl, isopropyl, etc.),
Phenyl groups, halogen atoms (eg fluoro, chloro,
Iodine, etc.), nitro group, cyano group, hydroxy group, C
_1-4 alkoxy group (eg, methoxy, ethoxy, n-
Propoxy, n-butoxy, isopropoxy, etc.) C
_1-4 alkylthio group (eg, methylthio, ethylthio, propylthio, isopropylthio, etc.), amino group, mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.) , C _1-4 alkylcarbonylamino group (eg, formylamino, acetylamino, propionylamino, butyrylamino, etc.), C
_1-4 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C _1-4
Alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), carboxyl group, C _1-6 alkylcarbonyl group (eg, formyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, etc.), C _1-4 alkylcarbonyloxy Group (eg, acetyl, ethylcarbonyloxy, etc.), 5- to 6-membered heterocyclic group containing 1 to 4 heteroatoms such as O, S, N (eg, pyridinyl, furyl, thiophenyl, etc.) and the like are used. To be Specific examples of the mono-substituted amino group (R ₇ NH-) include cyclohexylamino, phenylamino (anilino) and benzylamino, and specific examples of the di-substituted amino group (R ₈ R ₉ N-) include: Include dicyclohexylamino, diphenylamino, hexamethyleneimino (homopiperidinyl), 10,11-dihydro-5H-.
Dibenz (b, f) azepin-5-yl (Dba), morpholino, piperidino, methylpiperazino, 1- (2-
Pyrimidyl) piperazino and the like are more preferable.

In the formula [B], R ₂ and R ₅ each represent a hydrogen atom or a lower alkyl group. Here, the lower alkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec-.
Butyl, tert-butyl, n-pentyl, isoamyl, tert-amyl, neopentyl, n-hexyl and the like are used. As R ₂ and R ₅ , a hydrogen atom or a C _1-3 alkyl group such as methyl is particularly preferable.

In the formula [B], R ₃ represents an aliphatic group which may contain an oxygen atom or a sulfur atom. The aliphatic group is preferably an alkyl group, a cycloalkyl group or a cycloalkylalkyl group, and methylene (CH2) at any position other than the α-position of these aliphatic groups may be replaced by an oxygen atom or a sulfur atom. Good. As the alkyl group, a linear or branched alkyl group having 1 to 8 carbon atoms is preferable, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec-.
Butyl, tert-butyl, n-pentyl, isoamyl, tert-amyl, neopentyl, n-hexyl,
n-heptyl, n-octyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl,
3-methoxypropyl, 3-ethoxypropyl, methylthiomethyl, ethylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 3-methylthiopropyl,
3-Ethylthiopropyl and the like are used, but especially an alkyl group having 1 to 6 carbon atoms (for example, methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isoamyl, tert-amyl, neopentyl, n
-Hexyl) is preferred. The cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, cycloheptyl, cyclooctyl, tetrahydrofuran-2-yl, tetrahydrothiophen-2-yl and the like are used. As the cycloalkylalkyl group, a linear or branched alkyl group having 1-8 carbon atoms substituted with a cycloalkyl group having 3-8 carbon atoms is preferable, and examples thereof include cyclopentylmethyl, cyclohexylmethyl, and 2- (cyclopentyl). ) Ethyl, 2- (cyclohexyl) ethyl, cyclopentylthiomethyl, cyclohexylthiomethyl and the like are used. R ₃ is more preferably a C _1-6 alkyl group, and among them, a butyl group (n-butyl, isobutyl, sec-butyl, ter
Most preferred is t-butyl). Although the carbon atom to which R ₃ is bonded is an asymmetric carbon, the compound [B] of the present invention has R ₃
Shows a significant endothelin receptor antagonism by being in the L configuration. In the formula [B], R ₄ represents an optionally substituted heterocycle-lower alkyl group. Here, the heterocyclic-lower alkyl group means a lower alkyl group substituted with a heterocyclic group, which is a 5-6 membered heterocyclic group containing 1-4 heterocyclic ring atoms such as O, S and N. Heterocyclic groups (e.g. pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, piperidinyl, pyrazolyl, pyrazolidinyl, pyridyl, pyrimidyl, pyrazinyl, piperazinyl, pyridazinyl, triazolyl, tetrazolyl, dihydrotriazinyl, pyridyl, oxazolyl, isoxazolyl, isoxazolyl, isoxazolyl, isoxazolyl, oxazolyl. , Furyl, thienyl, thiazolyl, isothiazolyl, thiazolinyl,
Thiadiazolyl, triazolidinyl, etc.) or those which are fused with other rings (eg, benzene ring, etc.) (eg, indolyl, isoindolyl, etc.)
Indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benztriazolyl, tetrazolopyridyl, tetrazolopyridazinyl, benzoxazolyl, benzoxadiazolyl, benzthiazolyl,
Benzthiadiazolyl) is preferred. These heterocyclic groups may have 1 to 3 substituents, and as a substituent on a carbon atom, C _1-6 alkyl (methyl, ethyl, n-propyl, n-butyl etc.), halogen ( Fluorine, chlorine, bromine, iodine, etc.), hydroxyl, carboxyl, C _1-6 alkoxy (methoxy, ethoxy, n-
Propoxy, n-butoxy, etc.), C _1-6 alkylcarbonyl (formyl, acetyl), etc., also as C _1-6 alkyl (methyl, ethyl, n
-Propyl, n-butyl, etc.), C _1-6 alkylcarbonyl (formyl, acetyl, etc.), hydroxy-C _1-6
Examples thereof include alkyl (hydroxymethyl, 2-hydroxyethyl, etc.). On the other hand, the lower alkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert. -Butyl, n-pentyl, isoamyl, t
ert-amyl, neopentyl, n-hexyl and the like are used. Therefore, the heterocycle-lower alkyl group is more preferably a heterocycle-C _1-6 alkyl group, and examples thereof include 2-pyridyl-C _1-6 alkyl (for example, 2-pyridylmethyl, 2- (2 -Pyridyl) ethyl etc.), 3
-Pyridyl-C _1-6 alkyl (eg, 3-pyridylmethyl, 2- (3-pyridyl) ethyl, etc.), 4-pyridyl-C _1-6 alkyl (eg, 4-pyridylmethyl, 2
-(4-pyridyl) ethyl etc.), imidazole-2-
Yl-C _1-6 alkyl (eg, imidazol-2-ylmethyl, 2- (imidazol-2-yl) ethyl, etc.), imidazol-4-yl-C _1-6 alkyl (eg, imidazol-4-ylmethyl, 2 -(Imidazol-4-yl) ethyl etc.), indol-3-yl-
C _1-6 alkyl (eg, indol-3-ylmethyl, 2- (indol-3-yl) ethyl, etc.), N-
Methylindol-3-yl-C _1-6 alkyl (eg N-methylindol-3-ylmethyl, 2- (N
-Methylindol-3-yl) ethyl etc.), N-ethylindol-3-yl-C _1-6 alkyl (eg,
N-ethylindol-3-ylmethyl, 2- (N-ethylindol-3-yl) ethyl, etc.), N-hydroxymethylindol-3-yl-C _1-6 alkyl (eg, N-hydroxymethylindol-3 -Ylmethyl, 2- (N-hydroxymethylindol-3-yl) ethyl, etc.), N-formylindol-3-yl
-C _1-6 alkyl (eg N-formylindole-
3-ylmethyl, 2- (N-formylindole-3-
Yl) ethyl etc.), thiazol-4-yl-C _1-6 alkyl (eg, thiazol-4-ylmethyl, 2-
(Thiazol-4-yl) ethyl etc.), 5-fluoroindol-3-yl-C _1-6 alkyl (eg 5-
Fluoroindol-3-ylmethyl, 2- (5-fluoroindol-3-yl) ethyl, etc.) and the like are used. R ₄ is preferably an optionally substituted indol-3-yl-C _1-6 alkyl, among which indol-3-ylmethyl and N-methylindol-3-
Most preferred are ilmethyl, N-hydroxymethylindol-3-ylmethyl and the like. The carbon atom to which R ₄ is bonded is an asymmetric carbon, but in the present invention, R ₄ has a D-coordinate and thus exhibits a marked endothelin receptor antagonistic action.

In the formula [B], X represents a group having an aromatic ring. Here, the group having an aromatic ring is, for example, a group formed by removing one hydrogen atom of the α-amino group from an α-amino acid having at least one aromatic ring group, or an alkyl substituted with an aromatic ring group. Examples include amino groups. That is, it is preferable that CO and X are bound by an amide bond. Examples of the aromatic ring group include an optionally substituted aromatic hydrocarbon group or aromatic heterocyclic group. As the aromatic hydrocarbon group, C6-15 ones such as phenyl and α-naphthyl are used. These aromatic hydrocarbon groups are, for example, halogen atoms (eg, fluoro, chloro, bromo, iodo), hydroxy groups, C _1-6 alkyl (eg, methyl, ethyl), C
_1-6 alkoxy group (eg, methoxy, ethoxy), carboxyl group, C _1-6 alkylcarbonyl (eg, formyl,
It may have 1 to 3 substituents selected from acetyl), C _1-6 alkoxycarbonyl (eg, acetoxy) and the like. Examples of the optionally substituted aromatic hydrocarbon group include phenyl, 4-fluorophenyl,
4-chlorophenyl, 4-bromophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-methylphenyl, 1-naphthyl, 2-naphthyl and the like are commonly used.
The aromatic heterocyclic group is a 5-6 membered one containing 1-4 heterocyclic ring atoms such as O, S and N, or these are further condensed with another aromatic ring (for example, benzene ring). Those (for example, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, thiazol-4-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, indol-3-yl, N- Methylindol-3-yl,
2-quinolyl, quinoxalin-2-yl, etc.) are preferred. These aromatic heterocyclic groups may have, for example, 1 to 3 substituents similar to the substituents that the aromatic hydrocarbon group may have.

The α-amino acids of the α-amino acids having at least one aromatic ring group are substituted with the above-mentioned substituents, those protected with a protecting group, and
Also included are those in which at least one aromatic ring group present in the α-amino acid is an aromatic ring contained in this substituent or protecting group. The α-amino acid is a naturally occurring α-amino acid (eg, Gly, Ala, Val, Leu, Ile, S.
er, Thr, Glu, Asn, Phe, Trp, Me
t, His, Cys, Arg, Asn, Gln, Ty
r, (I) Tyr, diiodo-Tyr, etc.), but also unnatural α-amino acids (eg Phg, C
ha, Nva, Nle, Pya (2), Pya (3), Th
i, etc.), and any of L-body, D-body, and DL-body. Examples of the substituent or protecting group of the α-amino acid mainly include a substituent or protecting group at the carboxyl group at the 1-position thereof, and an ester (for example, benzyl ester, diphenylmethyl ester, trityl ester, etc.) at this carboxyl group or Amides (for example, phenylamide, benzylamide, diphenylamide, dibenzylamide, 2-phenylethylamide, 2,2-diphenylethylamide, 1,2-diphenylethylamide, indol-3-ylmethylamide), 2- (Indol-3-yl) ethylamide and the like) are preferred. As the amide at the 1-position carboxyl group, an amide with another α-amino acid is also included in the present invention. When there is a carboxyl group in addition to the 1-position, an ester (eg, phenyl ester, benzyl ester, diphenylmethyl ester, trityl ester, etc.) or amide (eg, phenylamide, benzylamide, diphenylmethylamide, diphenylamide) in the carboxyl group , Dibenzylamide, 2-phenylethylamide, 2,2-diphenylethylamide, 1,2-diphenylethylamide, indol-3-ylmethylamide, 2- (indole-3
-Yl) ethylamide and the like). Further, it may be a substituent in a functional group other than a carboxyl group (for example, a hydroxyl group, a thiol group, an amino group, etc.), a protecting group, or a substituent on a carbon atom.

Specific examples of the "group formed by removing one hydrogen atom of the α-amino group from the α-amino acid having at least one aromatic ring" in X are, for example, -Phe-OH, -Tyr. -OH, -Trp-OH, -Phg-OH,-(mF) Tyr-
OH,-(pF) Phe-OH,-(p-Cl) Phe-OH,-(p-Me) Phe-OH, -T
rp (Me) -OH, -Trp (CHO) -OH, -Phe-Trp-OH, -Trp-Phe-OH,
-Tyr-Trp-OH, -Trp-Phe-OH,-(mF) Tyr- (pF) Phe-OH,-
Glu (OBzl) -OH, -Glu-OBzl, -Asp (OBzl) -OH, -Asp-OBz
l, -Asp-Asp (OBzl) -OH, -Glu (NBzl ₂ ) -OH, -Glu (NHBzl)-
OH, -Asp (NBzl ₂ ) -OH, -Asp (NHBzl) -OH, -Glu-NBzl ₂ , -G
lu-NHBzl, -Asp-NBzl ₂ , -Asp-NHBzl, -Glu-NHCHPhCH ₂ P
h, -Asp-NHCHPhCH ₂ Ph, -Glu-NHCH ₂ CHPh ₂ , -Asp-NHCH ₂ CH
Ph ₂ , -Glu (NHCHPhCH ₂ Ph) -OH, -Asp (NHCHPhCH ₂ Ph) -OH,-
Glu (NHCH ₂ CHPh ₂ ) -OH, -Asp (NHCH ₂ CHPh ₂ ) -OH, -Glu (NHCH
₂ CH ₂ -Ind) -OH, -Asp (NHCH ₂ CH ₂ -Ind) -OH, -Glu-NHCH ₂ CH ₂
-Ind, -Asp-NHCH ₂ CH ₂ -Ind, -Trp-NH-Ind (OH), -Tyr-Iqu
(OH),-(I) Tyr-Phe-OH, -Trp-Trp-OH, -Tyr (Bzl) -Phe-O
H, -Tyr (Bzl) -Trp-OH,-(I) Tyr-Trp-OH,-(I) Tyr-Tyr-O
H, -Trp-His-OH, -His-Trp-OH, -Tyr-His-OH, -His-Tyr
-OH, -Phe-His-OH, -His-Phe-OH, -Phe-Trp-OH, -Phe-T
yr-OH, -Phe-Phe-OH, etc. are used. The constituent amino acids of these groups may be L-form, D-form or DL-form. X
More specifically, the alkylamino group of the “alkylamino group substituted with an aromatic ring group” in is, for example, C _1-10
It is an alkylamino group or a C _3-10 cycloalkylamino group. Aromatic ring groups are those alkylamino groups (eg, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, n -Hexylamino, n-
Decylamino, cyclopropylamino, cyclopentylamino, cyclohexylamino, cyclohexylmethylamino, 2-cyclohexylethylamino, etc.) substituted on the carbon or on the nitrogen. The aromatic ring group is as described above. Therefore, specific examples of the “alkylamino group substituted with an aromatic ring group” include, for example,
-NBzl ₂ , -NHBzl, -NHCHPhCH ₂ Ph, -NHCH ₂ CHPh ₂ , -NHCH ₂ CH
_2- Ind or the like is used.

In the formula [B], R ₆ represents a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted aromatic ring group. Here, the lower alkyl group has 1 carbon atom
A linear or branched alkyl group of -6 is preferable, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and ter.
T-butyl, n-pentyl, isoamyl, tert-amyl, neopentyl, n-hexyl and the like are used.
These lower alkyl groups may have 1 to 3 substituents, and examples of the substituent include an aromatic ring group (for example, phenyl, naphthyl, indenyl, furyl, thienyl, pyridyl, quinolyl, pyranyl, C _6-15 aromatic hydrocarbon groups such as imidazolyl, pyrimidyl, purinyl and indolyl and heterocyclic ring atoms such as O, S and N
A 5- or 6-membered aromatic heterocyclic group containing four or those which are further condensed with another aromatic ring (for example, a benzene ring), a sulfur-containing group (for example, thione, mercapto,
Methylthio, ethylthio, phenylthio, etc.), oxygen-containing groups (eg, ketone, hydroxy, methoxy, ethoxy, phenoxy, benzyloxy, etc.), nitrogen-containing groups (amino, N-methylamino, N-ethylamino, guanidino, etc.) Used. Further, the aromatic ring group is preferably an optionally substituted aromatic hydrocarbon group or aromatic heterocyclic group. Such an aromatic hydrocarbon group has 6-12 carbon atoms (for example, phenyl, 1-naphthyl,
2-naphthyl etc.) is O as an aromatic heterocyclic group,
5- to 6-membered rings containing 1-4 heterocyclic ring atoms such as S and N, or those fused with other rings (eg, benzene ring) (eg, furyl, thienyl,
Pyridyl, thiazolyl, imidazolyl, indolyl, etc.) are preferred. Substituents for these aromatic hydrocarbon groups or aromatic heterocyclic groups include C _1-6 alkyl (methyl,
Ethyl, n-propyl, n-butyl, etc.), halogen (fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkoxy (methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, etc.) , C
_1-6 alkylthio (methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, ter
t-butylthio, etc.), C _1-6 alkylcarbonyl (formyl, acetyl), C _1-6 alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, etc.) and the like, and the number of substituents Is 1 to 3. R ₆
Especially include lower alkyl groups (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,
a C _1-6 alkyl group such as n-pentyl, isoamyl, tert-amyl, neopentyl, n-hexyl), for example, containing 1-4 heterocyclic ring atoms such as O, S, N
6-membered aromatic heterocyclic group (for example, furyl, thienyl,
Pyridyl) or an aromatic heterocyclic group [eg O,
5- to 6-membered rings containing 1-4 heterocyclic ring atoms such as S and N, or those fused with other rings (eg, benzene ring) (eg, furyl, thienyl, pyridyl, Thiazolyl, imidazolyl, indolyl, etc.)]]-Substituted lower alkyl group (eg, 2
-Pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, indol-3-ylmethyl, N-methylindol-3-ylmethyl, N-formylindole-3
-Ylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-imidazolylmethyl, etc.) are preferred. The carbon atom to which R ₆ is bonded is an asymmetric carbon, and in the present invention, it may be L coordination, D coordination, or DL coordination, but D coordination is more preferred. In the formula [I], n represents 0 or an integer of 1 or more, but an integer of 0 or 1-4 is particularly preferable, and 0 is most preferable. -N when n is 0
The portion of (R ₅ -CH (R ₆ )-(CH ₂ ) n-CO- is represented as -N (R ₅ ) -CH (R ₆ ) -CO-, so this portion is an α-amino acid residue. (For example,
Ala, Val, Leu, Ile, Trp, Pya
(2), Pya (3), etc.), especially Ala, T
rp, Pya (2) and Pya (3) are preferred. In the formula [I], m represents an integer of 2 or more, but an integer of 2-6 is particularly preferable. -NH- (CH ₂ ) m-CO- is βAla when m = 2
, M = 3 represents GABA, and m = 5 represents εAhx.
If the peptide [B] is an acidic compound, a salt with a base,
If the peptide [B] is a basic compound, a salt with an acid is used. Examples of the salt of peptide [B] with a base include, for example, alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium salt, organic base salts (pyridine salt, Triethylamine salt etc.) and the like are used.
Examples of the salt of peptide [I] with an acid include, for example, inorganic acid salts (eg, hydrochloride, sulfate, nitrate, etc.), organic acid salts (eg, acetate, oxalate, paratoluenesulfonate, etc.) Are used.

[EP-A-0,499,266] Formula [C]

[0133]

[Chemical formula 45]

[In the formula, M represents a mercaptoacyl group,
P, Q, R, S, T, U, V, W, X, Y, and Z each represent an amino acid residue, and the amino acid side chain of Y is a substituted saturated aliphatic hydrocarbon group having 1 to 15 carbon atoms or (1S) -1-Methylpropyl group is an unsubstituted saturated aliphatic hydrocarbon group having 4 to 15 carbon atoms]
Or a pharmacologically acceptable salt thereof. Specifically, the peptides or pharmacologically acceptable salts thereof shown in Examples in EP-A-0,499,266 are used. In the peptide [C] of the present invention, the saturated aliphatic hydrocarbon group having 1 to 15 carbon atoms as the amino acid side chain of Y is a linear or branched alkyl, cycloalkyl or cycloalkylalkyl group. The alkyl group is preferably a C1 to C10 alkyl group, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-. Hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like can be mentioned. As the cycloalkyl group, a C ₃ to C ₁₀ cycloalkyl group is preferable, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and norbornyl. Cycloalkyl - is preferably C ₃ -C _{1 0} cycloalkyl -C ₁ -C ₆ alkyl as the alkyl group, and examples thereof cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 1-cyclopentyl Ethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, 4-
Cyclohexylbutyl and 5-cyclohexylpropyl are mentioned.

The above saturated hydrocarbon group is substituted,
As this substituent, a sulfur-containing group (thione, mercapto,
Methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, t-butylthio, phenylthio, cyclopentylthio, cyclohexylthio, thienyl, etc.), oxygen-containing groups (ketone, hydroxy, methoxy, ethoxy, n-propoxy, Isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentyloxy, cyclohexyloxy, phenoxy, benzyloxy, furyl, etc., nitrogen-containing groups (amino, N-methylamino, N-ethylamino, Nn-
Propylamino, N-isopropylamino, Nn-butylamino, N-isobutylamino, Nt-butylamino, Nn-pentylamino, Nn-hexylamino, N-cyclohexylamino, N, N- Dimethylamino, N, N-diethylamino, N, N-di-n-propylamino, N, N-di-iso-propylamino, N, N
-Di-n-butylamino, N, N-di-iso-butylamino, N, N-di-t-butylamino, N, N-di-n
-Pentylamino, N, N-di-n-hexylamino,
N, N-dicyclohexylamino, nitro, guanidino, pyrrolidino, piperidino, indolyl, imidazolyl, etc.), aromatic hydrocarbon group (for example, phenyl, 1-naphthyl, 2-naphthyl), halogen (chloro, bromo,
Such as fluoro). (1 as Y '
Examples of the non-substituted saturated aliphatic hydrocarbon group having 4 to 15 carbon atoms other than S) -1-methylpropyl group include an alkyl group, a cycloalkyl group and a cycloalkyl-alkyl group, and these alkyl groups are linear. Alternatively it can be branched. C ₄ -C as the alkyl group
₁₀ alkyl groups are preferred, examples of which include n-
Butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like can be mentioned. The cycloalkyl group is preferably a cycloalkyl group having 4 to 10 carbon atoms, and examples thereof include cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and norbornyl. The cycloalkyl-alkyl group may be C ₃ -C ₁₀ cycloalkyl-
C ₁ -C ₆ alkyl is preferable, and examples thereof include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,
1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 2,2-dicyclopentylethyl, 2,2-dicyclohexylethyl, 3-cyclohexylpropyl, 4
-Cyclohexylbutyl and 5-cyclohexylpropyl. The side chain of the amino acid of Y is more preferably a hydrocarbon group branched at the carbon atom at the β-position, and examples thereof include isobutyl, neopentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 2-cyclohexylpropyl, 2,2-dicyclohexylethyl, 2-mercaptopropyl, 2-thienylmethyl, 2-hydroxypropyl, 2-furylmethyl,
Such as 3-indolylmethyl, 4-imidazolylmethyl and benzyl.

In the present invention, the optionally substituted mercaptoacyl group represented by M is an acyl group derived from a carboxylic acid having a mercapto group, and the carboxylic acid is an aliphatic, alicyclic or aromatic group. There are things. The aliphatic mercaptoacyl group is mercapto C
_{A 2-} C ₁₀ alkanoyl group is preferable, and examples thereof include 3-mercaptopropionyl and 4-mercaptobutyryl. The alicyclic mercaptoacyl group is preferably mercapto C ₃ -C ₈ cycloalkylcarbonyl, such as 3-mercaptocyclopentylcarbonyl. The aromatic mercaptoacyl group is preferably, for example, a mercapto C ₆ -C ₁₄ arylcarbonyl group, and examples thereof include 4-mercaptobenzoyl, 4-mercaptophenylacetyl and 3-mercapto-3-phenylpropionyl. Above all, the above aliphatic,
Alicyclic compounds are preferred. The mercaptoacyl group may be substituted. Examples of the substituent on the mercaptoacyl group include an amino group and a hydroxyl group, and a mercaptoacyl group in which the α-position of the acyl group is substituted with an amino group is more preferable. Therefore, preferred examples include Cys, homocysteine, 3-mercapto-D-valine (penicillamine) and the like. A 3-mercaptopropionyl group is an unsubstituted mercaptoacyl group, and Cys is a most preferred example of a substituted mercaptoacyl group.

In the present invention, P, Q, R, S, T,
The amino acid residues represented by U, V, W, X, Y and Z are
The residue may be a natural amino acid residue or a non-natural amino acid residue, and may be any of L-form, D-form and DL-form. Therefore, P, Q, R, S, T, U, V, W,
X, Y, Z are respectively

[0138]

[Chemical formula 46]

The compound of the formula [C] is represented by [C ′]

[0140]

[Chemical 47]

It can be expressed as In the formula [C '], P', Q ', R', S ', T', U ', V', W ',
X ′ and Z ′ each represent a hydrogen atom or an optionally substituted hydrocarbon group having 1 to 15 carbon atoms, Y ′ corresponds to the amino acid side chain of Y described above, and has 1 carbon atom which is substituted.
To 15 saturated aliphatic hydrocarbon groups or (1S) -1
-A substituted non-substituted saturated aliphatic hydrocarbon group having 4 to 15 carbon atoms other than methylpropyl group. Examples of the hydrocarbon group having 1 to 15 carbon atoms include an aliphatic hydrocarbon group, an aromatic hydrocarbon group and an aliphatic aromatic hydrocarbon group. The aliphatic hydrocarbon group for P'to X'and Z'may be a saturated or unsaturated linear, branched or cyclic hydrocarbon group, and examples thereof include methyl, ethyl and n-. Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, cyclopentyl,
Examples thereof include n-hexyl, cyclohexyl, n-heptyl, cycloheptyl, n-octyl, n-nonyl, n-decyl, cyclopentylmethyl and cyclohexylmethyl. Examples of the substituted aliphatic hydrocarbon group include methylthiomethyl, ethylthiomethyl, n-propylthiomethyl, isopropylthiomethyl, n-butylthiomethyl,
t-butylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 2-t-butylthioethyl, mercaptomethyl, 1-mercaptoethyl, 2-mercaptoethyl, phenylthiomethyl, 1-phenylthioethyl, 2
-Phenylthioethyl, benzylthiomethyl, 4-methoxyphenylthiomethyl, 4-methoxybenzylthiomethyl, 4-methylbenzylthiomethyl, 4-nitrobenzylthiomethyl, 4-pyridylbenzylthiomethyl, hydroxymethyl, 1-hydroxy Ethyl, 2-hydroxyethyl, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, t-butoxymethyl, n-pentyloxymethyl, cyclopentyloxymethyl, n-hexyloxymethyl, cyclohexyloxy Methyl, 1-methoxyethyl, 1-ethoxyethyl, 1-propoxyethyl, 1
-Isopropoxyethyl, 1-n-butoxyethyl, 1
-Isobutoxyethyl, 1-t-butoxyethyl, phenoxymethyl, 1-phenoxyethyl, 2-phenoxyethyl, benzyloxymethyl, 2-benzyloxyethyl, carboxymethyl, 1-carboxyethyl, 2-
Carboxyethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, n-propoxycarbonylmethyl, isopropoxycarbonylmethyl, n-butoxycarbonylmethyl, isobutoxycarbonylmethyl, t-
Butoxycarbonylmethyl, n-pentyloxycarbonylmethyl, cyclopentyloxycarbonylmethyl,
n-hexyloxycarbonylmethyl, cyclohexyloxycarbonylmethyl, cycloheptyloxycarbonylmethyl, cyclooctyloxycarbonylmethyl,
Carboxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, n-propoxycarbonylethyl, isopropoxycarbonylethyl, n-butoxycarbonylethyl, isobutoxycarbonylethyl, t-
Butoxycarbonylethyl, n-pentyloxycarbonylethyl, cyclopentyloxycarbonylethyl,
n-hexyloxycarbonylethyl, cyclohexyloxycarbonylethyl, cycloheptyloxycarbonylethyl, cyclooctyloxycarbonylethyl,
2-aminoethyl, 2- (N-methylamino) ethyl,
2- (N, N-dimethylamino) ethyl, 3-aminopropyl, 3- (N, N-diethylamino) propyl, 2
-Guadininoethyl, 3-guanidinopropyl, aminocarbonylmethyl, N-methylaminocarbonylmethyl, N-ethylaminocarbonylmethyl, N-n-propylaminocarbonylmethyl, N-isopropylaminocarbonylmethyl, Nn-butylaminocarbonylmethyl , N-isobutylaminocarbonylmethyl, Nt
-Butylaminocarbonylmethyl, N-n-pentylaminocarbonylmethyl, N-isopentylaminocarbonylmethyl, N-neopentylaminocarbonylmethyl, Nn-hexylaminocarbonylmethyl, N-cyclohexylaminocarbonylmethyl, N, N -Dimethylaminocarbonylmethyl, N, N-diethylaminocarbonylmethyl, N, N-di-n-propylaminocarbonylmethyl, N, N-diisopropylaminocarbonylmethyl, N, N-di-n-butylaminocarbonylmethyl, N , N-di-isobutylaminocarbonylmethyl, N, N-di-t-butylaminocarbonylmethyl,
N, N-di-n-pentylaminocarbonylmethyl,
N, N-di-isopentylaminocarbonylmethyl,
N, N-di-neopentylaminocarbonylmethyl,
N, N-di-n-hexylaminocarbonylmethyl,
N, N-dicyclohexylaminocarbonylmethyl, pyrrolidinocarbonylmethyl, piperidinocarbonylmethyl, aminocarbonylethyl, N-methylaminocarbonylethyl, N-ethylaminocarbonylethyl, N-
n-propylaminocarbonylethyl, N-isopropylaminocarbonylethyl, N-n-butylaminocarbonylethyl, N-isobutylaminocarbonylethyl, Nt-butylaminocarbonylethyl, Nn-
Pentylaminocarbonylethyl, N-cyclopentylaminocarbonylethyl, Nn-hexylaminocarbonylethyl, N-cyclohexylaminocarbonylethyl, N, N-dimethylaminocarbonylethyl, N,
N-diethylaminocarbonylethyl, N, N-di-n
-Propylaminocarbonylethyl, N, N-diisopropylaminocarbonylethyl, N, N-di-n-butylaminocarbonylethyl, N, N-diisobutylaminocarbonylethyl, N, N-di-t-butylaminocarbonylethyl, N, N-di-n-pentylaminocarbonylethyl, N, N-dicyclopentylaminocarbonylethyl, N, N-di-n-hexylaminocarbonylethyl, N, N-dicyclohexylaminocarbonylethyl, 3-indolylmethyl , 4-imidazolylmethyl, 2-thienylmethyl, 2-furylmethyl, pyrrolidinocarbonylethyl, piperidinocarbonylethyl and the like.

The aromatic hydrocarbon group or the aliphatic aromatic hydrocarbon group for P'to X'and Z'is as follows.
For example, phenyl, 1-naphthyl, 2-naphthyl, phenylmethyl, 1-phenylethyl, 2-phenylethyl, 1-naphthylmethyl, 2-naphthylmethyl, 9-anthranylmethyl and the like can be mentioned. Examples of the substituted aromatic hydrocarbon group and aliphatic aromatic hydrocarbon group include 4
-Hydroxyphenyl, 4-hydroxyphenylmethyl, 4-methoxyphenylmethyl, 4-ethoxyphenylmethyl, 4-n-propoxyphenylmethyl, 4-isopropoxyphenylmethyl, 4-n-butoxyphenylmethyl, 4-isobutoxyphenyl Methyl, 4-t-
Butoxyphenylmethyl, 4-n-pentyloxyphenylmethyl, 4-cyclopentyloxyphenylmethyl, 4-n-hexyloxyphenylmethyl, 4-cyclohexyloxyphenylmethyl, 4-aminophenylmethyl, 4-dimethylaminophenylmethyl, 4 -Diethylaminophenylmethyl, 4-di-n-propylaminophenylmethyl, 4-diisopropylaminophenylmethyl, 4-di-n-butylaminophenylmethyl, 4
-Pyrrolidinophenylmethyl, 4-piperidinophenylmethyl, 4-nitrophenylmethyl, 4-fluorophenylmethyl, 3-fluorophenylmethyl, 2-fluorophenylmethyl, 4-chlorophenylmethyl, 3-chlorophenylmethyl, 2- Chlorophenylmethyl and the like can be mentioned. Y ′ (corresponding to the amino acid side chain of Y) is a substituted saturated aliphatic hydrocarbon group having 1 to 15 carbon atoms or a non-substituted saturated aliphatic hydrocarbon group having 4 to 15 carbon atoms other than (1S) -1-methylpropyl group. It is an aliphatic hydrocarbon group.

The above-mentioned amino acid residues P to Z (that is, P'to Z ') will be described more specifically and preferably as follows. P is an amino acid residue having an alkyl group which may be substituted as an amino acid side chain (P ′), and the substituent is preferably a hydroxyl group, and specific examples thereof include Ser, Thr and Ala. . As Q, for example, Ser, Thr, Ph
e and Ala are mentioned, and among them, Ser and Ala are preferable. R is an amino acid side chain (R ')
Is an amino acid residue having an alkyl group which may be substituted as, a hydroxyl group is preferable as the substituent,
Specific examples include Ser, Thr, and Ala.
S is a lipophilic (lipophili) as an amino acid side chain (S ').
an amino acid residue having part c), for example Le
Specific examples include u, Ala, Tyr, Trp, and Met, and among them, Leu is preferable. As T, Me
Examples thereof include t, Leu, Lys, Ala, Nle, Glu and the like, and among them, Met, Ala, Nle and the like are preferable. U
Examples include Lys, Ala, and Glu. As V, aromatic amino acids are preferable, and among them, monocyclic ones are more preferable than bicyclic ones, and Phe, T
In addition to yr, Trp is preferable. W
Examples include Gln and the like in addition to Leu. As Z, aromatic amino acids are preferable, and among them, bicyclic ones are preferable, and in addition to Trp, those having a substituent on Trp [for example, N (indole) -formyltryptophan], 3- (1-naphthyl) alanine. , 3- (2-naphthyl) alanine and the like are preferred. Since the S—S bond is oxidized during synthesis, tryptophan, which is susceptible to decomposition by oxidation, is often used instead of the N (indole) -formyl derivative or the like. As X, those other than Asp are preferable, and among them, an amino acid residue having a hydroxyl group is particularly preferable because of its strong binding affinity to the endothelin receptor, and examples thereof include Ser and Thr. In addition to these, Asn, Gly and the like are also preferably used amino acid residues. Y is an amino acid side chain (Y ')
Amino acid residue branched at position 2 of, for example, Leu, C
Ha, Phe, γLeu, Asn and the like are preferred. The present invention is essentially characterized by the substitution (Y) at the 19-position. Furthermore, the combination of the substitution at the 19-position and the substitution at the 18-position is also important, and the positions 18--19 are Thr-Leu, Thr-γLeu, Thr-Ch.
a, Thr-Phe, Thr-Asn, Ser-Le
A combination of u, Asn-Leu, Gly-Leu, etc. is a preferred example. Among them, Thr-Leu, Thr-γLe
The combination of u, Thr-Cha is particularly preferred.

[0144] Specific examples of the peptide [C] of the present invention, for example, 1 CysSerCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviated [Thr18, Leu19] ET-1: SEQ ID NO: 1) 2 CysSerCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuThrChaIleTrp (abbreviated [Thr18, Cha19] ET-1: SEQ ID NO: 2 ) 3 CysSerCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuThrPheIleTrp (abbreviated [Thr18, Phe19] ET-1: SEQ ID NO: 3) 4 CysSerCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuThrγLeuIleTrp (abbreviated [Thr18, γLeu19] ET-1: SEQ ID NO: 4) 5 CysSerCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuThrAsnIleTrp (abbreviated [Thr18, Asn19] ET-1: SEQ ID NO: 5) 6 CysSerCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuSerLeuIleTrp (abbreviated [Ser18, Leu19] ET-1: SEQ ID NO: 6) 7 CysSerCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuAsnLeuIleTrp (abbreviated [Asn18, Leu19] ET-1: SEQ ID NO: 7) 8 CysSerCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLe UGlyLeuIleTrp (abbreviated [Gly18, Leu19] ET-1: SEQ ID NO: 8) 9 CysThrCysPheThrTyrLysAspLysGluCysValTyrTyrCysHisLeuThrLeuIleTrp (abbreviated [Thr18, Leu19] ET-3: SEQ ID NO: 9) 10 CysSerCysSerSerLeuMetAspAlaGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviated [Ala9, Thr18, Leu19] ET-1: SEQ ID NO: 10) 11 MprSerCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviated [Mpr1, Thr18, Leu19] ET-1: SEQ ID NO: 11) 12 CysAlaCysSerSerLeuMetAspLysGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviated [Ala2, Thr18, Leu19] ET-1: SEQ ID NO: 12) 13 CysSerCysAlaSerLeuMetAspLysGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviated [Ala4, Thr18, Leu19 ] ET-1: SEQ ID NO: 13) 14 CysSerCysSerAlaLeuMetAspLysGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviated [Ala5, Thr18, Leu19] ET-1: SEQ ID NO: 14) 15 CysSerCysSerSerAlaMetAspLysGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviated [Ala6, Thr18, Leu19] ET-1: SEQ ID NO: 15) 16 CysSerCysSerSerLeuAlaAspLys JieruyushiwaiesubuieierutiwairPheCysHisLeuThrLeuIleTrp (abbreviated [Ala7, Thr18, Leu19] ET-1: SEQ ID NO: 16) 17 CysSerCysSerSerLeuNleAspLysGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviated [Nle7, Thr18, Leu19] ET-1: SEQ ID NO: 17) 18 CysSerCysSerSerTrpLeuAspLysGluCysValTyrPheCysHisLeuThrLeuIleTrp (abbreviated [Thr18, Leu19] ET-2: Sequence number 18) etc. are mentioned.

[WO91 / 13089] General Formula [D]

[0146]

[Chemical 48]

[Wherein A, B, C, D, E and F are amino acid residues, and (i) A = Ser, C = Ser, D = Le.
u, E = Met and F = Phe, (ii) A = Ser, B = Ser,
C = Ser, D = Trp, E = Leu and F = Phe, or (ii
i) A = Thr, B = Phe, C = Thr, D = Tyr, E = Lys and F = Tyr, and W, X, Y and Z are amino acid residues of W and Y At least one is an amino acid residue other than an L-alanine residue or an L-cysteine residue, X is an amino acid residue other than an L-lysine residue, or Z is an L-aspartic acid residue. The amino acid residue of the peptide derivative] or a pharmaceutically acceptable salt thereof. Specifically,
The peptide derivative shown in the examples of Japanese Patent Application No. 3-503831 (WO91 / 13089) or a pharmaceutically acceptable salt thereof is used.

[0148] [EP-A-436,189] formula [E] ^{Cyclo (-X 1 -X 2 -X 3} -X 4 -X 5) [E] (wherein, X ⁿ (n is 1 to 5 Represents an amino acid, X ¹ represents D-Phe, D-Tyr, D-Tha, D-Tz.
a, D-Nal, D-Bta, D-Trp, D-Trp (O), D-Trp
(CHO) or D-Trp [(CH ₂ ) mCOR ¹ ], wherein m is 0 to 6
R ¹ represents a hydroxyl group, a C _1-6 alkoxy group, an amino group or a C _1-6 monoalkylamino group. X ² is D
-Asp, shows a D-Glu or _{D-Cys (O 3 H)} . X ³ is Pro, Hy
p, Pip, Thz, β-Ala or Gly, Ala, α-Aba, Aib, Va
l, Nva, Leu, Ile, alle, Nle, Met, Met (O), Met (O ₂ ),
Phe, Tza, Tha, Tyr, Trp, His, Arg, Lys, Lys (CHO),
Orn, Orn (CHO), Asn, Gln, Asp, Glu, Cys (O ₃ H), Cys,
Ser or Thr, wherein the hydrogen atom on the α-amino group may have a group selected from the group consisting of an imidazolyl group, a carboxyl group, a sulfo group and a hydroxyl group, C _1-6 alkyl or C _{3-. 7 It} may be substituted with a cycloalkyl group. X ⁴ is D-Ala, D-Thr, D-αAba, D
-Val, D-Nva, D-Leu, D-Ile, D-alle, D-Nl
e, D-tertLeu, D-Cpg, D-Chg, D-Dpg, D-Pe
n, Aib, Ac3c, Ac4c, Ac5c, Ac6c, Ac7c, or D-Phg,
D-Thg, D-Fug, D-Tzg or D-Itg is shown, and α-
The hydrogen atom on the amino group may be substituted with a C1-3 alkyl group. X ⁵ is Pro, Pip, Thz, or His, Ala, αAb
a, Val, Nva, Leu, Ile, alle, Nle, Met, C3al, C4al,
C5al or C6al is shown, and the hydrogen atom on the α-amino group may be substituted with a C _1-6 alkyl group. ] The cyclic pentapeptide shown by these, or its pharmaceutically acceptable salt.
Specifically, the cyclic pentapeptide shown in the examples in EP-A-436,189 or a pharmaceutically acceptable salt thereof is used, and especially Cyclo (-D-Asp-Pro-D-Val -Leu-D-Trp-) Cyclo (-D-Cys (03H) -Pro-D-Val-Leu-D-Trp-) Cyclo (-D-Asp-Pro-D-Thg (2) -Leu-D -Trp-) Cyclo (-D-Asp-Pro-D-Cpg-Leu-D-Trp-) and the like are preferable.

[EP-A-457,195] Formula [F]

[0150]

[Chemical 49]

(In the formula, R ¹ represents a hydrogen atom or an acyl group. R ² represents a lower alkyl group, an optionally substituted ar (lower) alkyl group, cyclo (lower) alkyl (lower))
It represents an alkyl group or an optionally substituted heterocyclic (lower) alkyl group. R ³ represents an optionally substituted heterocyclic (lower) alkyl group or an optionally substituted ar (lower) alkyl group. R ⁴ represents a hydrogen atom or an optionally substituted lower alkyl group. R ⁵ represents a carboxyl group, a protected carboxyl group, a carboxy (lower) alkyl group or a protected carboxy (lower) alkyl group. R ⁶ represents a hydrogen atom or an optionally substituted lower alkyl group. R ⁷ represents a hydrogen atom or a lower alkyl group. The above-mentioned "lower" has 1 to 6 carbon atoms. A represents -O-, -NH-, a lower alkylamino group or a lower alkylene group. Provided that R ² is a (S) -isobutyl group, R ³ is an N- (dichlorobenzyloxycarbonyl) indol-3-ylmethylene group, R ⁴ is a methyl group, R ⁵ is a methoxycarbonyl group, and R ⁶ is When R ⁷ is a hydrogen atom and A is —NH—, it is a partial formula.

[0152]

[Chemical 50]

It has an absolute configuration of. ) A peptide represented by or a pharmaceutically acceptable salt thereof. Specifically, EP
-The peptides shown in the examples in A-457,195 or their pharmaceutically acceptable salts are used.

[EP-A-510,526] Formula [G]

[0155]

[Chemical 51]

(In the formula, R ¹ represents a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halogen atom or a trifluoromethyl group. R ² represents a halogen atom, a lower alkoxy group, a hydroxy lower alkoxy group or trifluoromethyl group. R ³ represents a hydroxy group, a halogen atom, an alkylthio group, a cycloalkyl group, a hydroxy lower alkyl group, a hydroxy lower alkoxy group, a hydroxyimino lower alkyl group, a lower alkenyl group, an oquino lower alkyl group, a trifluoromethyl group, A trifluoromethoxy group, a lower alkoxy group, a lower alkoxy lower alkoxy group or an aryl lower alkoxy group may be shown, and R ² and R ³ may form butadienyl, wherein R ⁴ is a lower alkyl group, an aryl group or a heteroaryl group. shown .R ⁵ is lower alkanoyl group, Shows the Nzoiru group, heterocyclic carbonyl group or a tetrahydropyran-2-yl group .R ⁶ is formula

[0157]

[Chemical 52]

Is shown. R ⁷ represents a lower alkoxy group or a nitro group. R ⁸ represents a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a nitro group, a hydroxy group, an amino group or a trifluoromethyl group,
R ⁷ and R ⁸ may form butadienyl. R ⁹ represents a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group or a trifluoromethyl group. R ¹⁰ represents a halogen atom, a lower alkyl group, a lower alkoxy group or a lower alkylthio group. The above-mentioned "lower" has 1 to 7 carbon atoms. X and Y each represent O, S or NH. n is 2, 3 or 4. ) Or a salt thereof. Specifically, the compounds or salts thereof shown in Examples in EP-A-510,526 are used.

[WO92 / 12991] Formula [H]

[0160]

[Chemical 53]

Wherein R ¹ is hydrogen or a metabolizable ester residue, R ³ is an optionally substituted aryl or an optionally substituted aromatic heterocycle, and one of X and Y is hydroxy. The other is hydrogen, or a triterpene derivative represented by hydrogen, or X and Y together represent oxo, and Z represents oxygen or two hydrogens. Specifically, WO92 / 129
The trityl pen derivative shown in the examples in 91 is used. [JP-A-4-288099] Formula [I]

[0162]

[Chemical 54]

(Wherein Xaa1 represents Tyr, Phe or Ala, Xaa2 represents Asp or Gly, and Xaa3 represents Trp.
Or Phe. ) An endothelin derivative represented by Specifically, the endothelin derivative shown in Examples in JP-A-4-288099 is used.

[EP-A-496,452] Formula [J]

[0165]

[Chemical 55]

A cyclic peptide represented by:

[EP-A-526,708] Formula [K]

[0168]

[Chemical 56]

(In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halogen atom or a trifluoromethyl group. R ² represents a hydrogen atom, a halogen atom, a lower alkoxy group, a trifluoro group. A methyl group or —OCH ₂ COOR ^a , R ³ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkylthio group, a trifluoromethyl group, a cycloalkyl group, a lower alkoxy group or a trifluoromethyl group, and R ² And R ³
May form butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy. R ⁴
Is a hydrogen atom, lower alkyl group, cycloalkyl group, trifluoromethyl group, lower alkoxy group, lower alkylthio group, lower alkylthio lower alkyl group, hydroxy lower alkyl group, hydroxy lower alkoxy group, lower alkoxy lower alkyl group, hydroxy lower alkoxy Lower alkyl group, hydroxy lower alkoxy lower alkoxy group, lower alkylsulfinyl group, lower alkylsulfonyl group, 2-methoxy-3-hydroxypropoxy group,
2-hydroxy-3-phenylpropyl group, amino lower alkyl group, lower alkylamino lower alkyl group, dilower alkylamino lower alkylamino group, lower alkylamino group, dilower alkylamino group, arylamino group, aryl group, arylthio Group, aryloxy group,
An aryl lower alkyl group or a heterocycle is shown. R ⁵ represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a benzoyl group, a heterocyclic carbonyl group, a heterocyclic methyl group or a tetrahydropyran-2-yl group. R ^{6 to} R ⁹ are hydrogen atom, halogen atom, trifluoromethyl group, lower alkyl group, lower alkoxy group, lower alkylthio group, hydroxy group, hydroxymethyl group, cyano group, carboxy group, formyl group, methylsulfinyl group, methyl A sulfonyl group, a methylsulfonyloxy group or a lower alkoxycarbonyloxy group is shown. R ⁷ together with R ⁶ or R ⁸ may form butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy. Z is-
O-, -S-, ethylene, vinylene, -CO-, -OC
HR10- or -SCHR ¹⁰ - show a. R ¹⁰ represents a hydrogen atom or a lower alkyl group. X and Y each represent O, S or NH. YR ⁵ represents a lower alkylsulfinyl group or —OCH ₂ CH (OR ^c ) CH ₂ OR ^d . R ^a , R ^b ,
R ^c and R ^d each represent a hydrogen atom or a lower alkyl group. R ^c and R ^d each represent methylene, ethylene or isopropylidene. n is 1, 2, or 3. ) The compound represented by. Specifically, EP-A-526,708
The compounds shown in the examples in are used.

[EP-A-460,679] Formula [L]

[0171]

[Chemical 57]

(In the formula, A ¹ is a group represented by the formula R ¹¹ —CO— (R ¹¹ is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a group represented by the formula Ar ^1- (CH ₂ ) p- Group (Ar ¹ represents a phenyl group, a furyl group or a thienyl group, p represents 0, 1 or 2), 1,3-dithio-2-ylidenemethyl group, or 1,3-dithiol-2-ylidene. (Lower alkoxycarbonyl) methyl group), a group represented by the formula R ¹² O—CO— (R ¹² represents a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, or a phenyl group), a formula ^{R 13 R 14 N-C (} = X 1) - group (X ¹ represented by represents an oxygen or sulfur atom, R ¹³ is a lower alkoxycarbonyl group, a cycloalkyl group, a lower alkynyl group, a 1-adamantyl group, Rorijino group, piperidino group, perhydro azepin-1-yl group, perhydro azo Shin-1-yl group, perhydro azo Nin-1-yl group,
Alternatively, a group represented by the formula Ar ² — (CH ₂ ) q— (Ar ²
Represents a phenyl group (wherein one or two hydrogen atoms on the benzene ring may be substituted with a halogen atom, a lower alkyl group or a lower alkoxy group, respectively), a furyl group or a thienyl group, and q is 0, 1 or 2 is shown. ) Is shown. R
¹⁴ is a hydrogen atom, a hydroxyl group, a cycloalkyl group, or the formula _{^{Ar 3 - (CH 2) r-}} (Ar 3 represents a phenyl group, a furyl group or a thienyl group, r is 1 or 2.)
R ¹³ and R ¹⁴ together with the adjacent nitrogen atom may form a 5- to 9-membered nitrogen-containing saturated heterocycle having 4 to 8 carbon atoms, and the heterocycle is formed. In the methylene group, one methylene group which is not adjacent to a nitrogen atom may be substituted with an oxy group, a thio group or a group represented by the formula —NR ¹⁵ — (R ¹⁵ is a lower alkyl group). 1 to 4 hydrogen atoms on a carbon atom of the ring may be substituted with a hydroxyl group or a lower alkyl group which may be substituted with hydroxyl, and further, two adjacent carbon atoms in the heterocycle may be replaced with each other. Atoms may form double bonds or benzofused rings. Also, R ¹³ and R
¹⁴ is a formula (LII) with B))

[0173]

[Chemical 58]

(Wherein R ¹⁶ represents a hydrogen atom, a lower alkyl group or a cycloalkyl group, and R 17 and R ¹⁸ each independently represent a hydrogen atom or a lower alkyl group). B represents an oxygen atom or a group represented by the formula —NR ² — (R ² represents a hydrogen atom or a methyl group), or forms a group represented by the above formula (LII) together with A ¹ . R
³ represents a lower alkyl group having 3 to 5 carbon atoms. R ⁴ represents a hydrogen atom or a methyl group. R ⁵ is a 3-indolylmethyl group, a (2,3-dihydro-2-oxo-3-indolyl) methyl group, and the indole ring has the formula R at the 1-position.
_{^{51 -CO- (CH 2) s- (}} R 51 is a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a benzyloxy group, an amino group or a mono-lower alkylamino group, s is 0 to 6 integer And when s is 0, R ⁵¹ represents a group other than a hydroxyl group) or a formula (R ⁵²
_{O) 2 P (= O)} - (CH 2) t- (R 52 represents a hydrogen atom, a lower alkyl group or a benzyl group, t is substituted with a group represented by showing) an integer of 0-6. 3-indolylmethyl group, any hydrogen atom on the benzene ring is represented by the formula R ⁵³ O
A benzyl group optionally substituted with a group represented by —CO— (CH ₂ ) u— (R ⁵³ represents a hydrogen atom or a lower alkyl group, and u represents an integer of 0 to 6), and on the benzene ring A benzyl group in which one or two hydrogen atoms of is substituted with a hydroxyl group, or two hydrogen atoms on the benzene ring are substituted with a hydroxyl group and a sulfo group,
A benzothienylmethyl group, a (1-oxo-3-benzothienyl) methyl group or a (1,1-dioxo-3-benzothienyl) methyl group. X ₂ represents an oxygen atom or a sulfur atom. A ₂ is the formula (LIII), (LIV), (LV),
Shows a group selected from the group consisting of (LVI), (LVII) and (LVIII).

[0175]

[Chemical 59]

Y is a sulfo group, a phosphono group, or a formula --CO ₂ R
A group represented by ⁹¹ (R ⁹¹ represents a hydrogen atom, a lower alkyl group or a benzyl group) or a formula —CONR ⁹² R ⁹³ (R ⁹²
Represents a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group, a phenylsulfonyl group in which any of 1 to 5 hydrogen atoms on the benzene ring may be substituted with a lower alkyl group or a halogen atom, or a carboxymethyl group. .. R ⁹³ represents a hydrogen atom or a lower alkyl group. )
Represents a group represented by. R ⁶¹ represents a hydrogen atom or a lower alkyl group, or represents a methylene group together with R ⁷¹ . R ⁷¹ is a hydrogen atom, a lower alkyl group optionally substituted with a hydroxyl group, a phenyl group, a thienyl group, or a phenyl lower alkyl group in which any hydrogen atom on the benzene ring may be substituted with a hydroxyl group or a benzyloxy group. Group, thienyl lower alkyl group, thiazolyl lower alkyl group, 4-imidazolylmethyl group, (lower alkyl-substituted 4-imidazolyl) -methylthiomethyl group, 3-indolylmethyl group, carbamoyl lower alkyl group or N-benzyloxycarbonyl-ω -Amino lower linear alkyl group, or methylene group together with R ⁶¹ . However, when R ⁶¹ is a lower alkyl group, R ⁷¹ represents a group other than a hydrogen atom. R ⁶²
Is a hydrogen atom, a phenyl group, a benzyl group, a carboxy group,
It represents a carbamoyl group or an N-phenylcarbamoyl group, or represents a single bond together with R ⁸ . R ⁷² represents a hydrogen atom, a lower alkyl group, a phenyl group, a benzyl group, a 3-indolylmethyl group, a carbamoyl group or an N-phenylcarbamoyl group. However, when R ⁶² is a group other than a hydrogen atom, R ⁶² is
⁷² represents a hydrogen atom or a lower alkyl group. R ⁸ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a hydroxyl group, or represents a single bond together with R ⁶² . V represents 3, 4 or 5. R ⁶³ represents a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a formula Ar ⁴ — (CH ₂ ) w- (Ar ⁴
Represents a phenyl group, a furyl group or a thienyl group, and w is 1
Or 2 is shown. ) Represents a group represented by. Z represents CH or N, and X represents 1, 2 or 3. ) A peptide derivative represented by or a pharmaceutically acceptable salt thereof. Specifically, the peptide derivative shown in the examples in EP-A-460,679 or a pharmaceutically acceptable salt thereof is used.

[WO92 / 20706] Formula AA ¹ -AA ² -AA ³ -AA ⁴ -AA ⁵ -AA ⁶ [M] (In the formula, AA ¹ is D-Dip, D-Bip, D-His, D- His
(Dnp), D-2-Nal, D-1-Nal, D-Phe, D-Pg
l, D-Tyr, D-Tyr (OMe), D-Tyr (OEt), D-Tyr (Ot
Bu), D-Trp, D-Trp (For), D-Tic, D-Tza, D-
Pyr, Ac-D-Dip, Ac-D-Bip, Ac-D-His, Ac-D
-His (Dnp), Ac-D-2-Nal, Ac-D-1-Nal, Ac-
D-Phe, Ac-D-Pgl, Ac-D-Tyr, Ac-D-Tyr (OM
e), Ac-D-Tyr (OEt), Ac-D-Tyr (OtBu), Ac-D-T
rp, Ac-D-Trp (For), Ac-D-Tic, Ac-D-Tza, Ac
-D-Pyr, Ada-D-Dip, Ada-D-Bip, Ada-D-Hi
s, Ada-D-His (Dnp), Ada-D-2-Nal, Ada-D-
1-Nal, Ada-D-Phe, Ada-D-Pgl, Ada-D-Ty
r, Ada-D-Tyr (OMe), Ada-D-Tyr (OEt), Ada-D-
Tyr (OtBu), Ada-D-Trp, Ada-D-Trp (For), Ada-
D-Tic, Ada-D-Tza, Ada-D-Pyr, Adoc-D-Di
p, Adoc-D-Bip, Adoc-D-His, Adoc-D-His (Dn
p), Adoc-D-2-Nal, Adoc-D-1-Nal, Adoc-D
-Phe, Adoc-D-Pgl, Adoc-D-Tyr, Adoc-D-Tyr
(OMe), Adoc-D-Tyr (OEt), Adoc-D-Tyr (OtBu), Ad
oc-D-Trp, Adoc-D-Trp (For), Adoc-D-Tic, Ad
oc-D-Tza, Adoc-D-Pyr, Boc-D-Dip, Boc-D
-Bip, Boc-D-His, Boc-D-His (Dnp), Boc-D-
2-Nal, Boc-D-1-Nal, Boc-D-Phe, Boc-D-
Pgl, Boc-D-Tyr, Boc-D-Tyr (OMe), Boc-D-Tyr
(OEt), Boc-D-Tyr (OtBu), Boc-D-Trp, Boc-D-
Trp (For), Boc-D-Tic, Boc-D-Tza, Boc-D-Py
r, Z-D-Dip, Z-D-Bip, Z-D-His, Z-D-
His (Dnp), Z-D-2-Nal, Z-D-1-Nal, Z-D
-Phe, Z-D-Pgl, Z-D-Tyr, Z-D-Tyr (OM
e), Z-D-Tyr (OEt), Z-D-Tyr (OtBu), Z-D-T
rp, Z-D-Trp (For), Z-D-Tic, Z-D-Tza, Z
-D-Pyr, Fmoc-D-Dip, Fmoc-D-Bip, Fmoc-D
-His, Fmoc-D-His (Dnp), Fmoc-D-2-Nal, Fmoc
-D-1-Nal, Fmoc-D-Phe, Fmoc-D-Pgl, Fmoc
-D-Tyr, Fmoc-D-Tyr (OMe), Fmoc-D-Tyr (OE
t), Fmoc-D-Tyr (OtBu), Fmoc-D-Trp, Fmoc-D-
Trp (For), Fmoc-D-Tic, Fmoc-D-Tza or Fmoc-
D-Pyr is shown. AA ² is Ala, Alg, Arg, Asn, Asp, Da
b, Glu, Gln, Gly, homoArg, homoGlu, homoLys, Ile,
Leu, D-Leu, Lys, Met, Met (O), Met (O2), Nva, Nl
Indicates e, Orn, Phe, Tyr or Val or lacks AA2. AA ³ is Asn, Asp, D-Asp, N-MeAsp, Glu, Gl
n, homoPhe, Phe or Tyr, or lacking AA ³ . AA ⁴ is Ala, Chx, Gly, Glu, Ile, D-Ile, Le
Indicates u, Nle, Nva or Val or lacks AA ⁴ . AA ⁵ is Ala, Chx, Gly, Ile, D-Ile, Leu, Nle,
Indicates Nva or Val or lacks AA ⁵ . AA ⁶ is 2-Nal, 1-Nal, Pyr, Trp, Tyr (OMe), Tyr (OEt), Ty
r (OtBu), Tyr, Trp-Gly, Trp-Asp, Trp (For), Dip, P
he, Bza or

[0178]

[Chemical 60]

Is shown. ) Or a pharmaceutically acceptable salt thereof. Specifically, WO92 / 2070
The compounds shown in Examples in 6 or pharmaceutically acceptable salts thereof are used.

[WO93 / 08799] Formula [N]

[0181]

[Chemical formula 61]

(In the formula, R ₁ is —X (CH ₂ ) nAr, —X
(CH ₂ ) nR ₈ or

[0183]

[Chemical formula 62]

R ₂ is hydrogen, Ar or (c)
P ₁ is —X (CH ₂ ) nR ₈ ; P ₂ is —X (C
H ₂₎ nR be ₈ or -XR ₉ Y; R ₃ and R ₅ are each independently hydrogen, R _11, OH, C _1-8 alkoxy, S (O) _q
R ₁₁ , N (R ₆ ) ₂ , Br, F, I, Cl, CF ₃ , NHC
OR _6, -XR ₉ Y or -X (CH ₂₎ nR ₈ [wherein -
The methylene group of X (CH ₂ ) nR ₈ has 1 or more-
(CH ₂ ) nAr group may be substituted]; R ₄ hydrogen, R ₁₁ , OH, C _1-5 alkoxy, S (O)
_{q represents} R ₁₁ , N (R ₆ ) ₂ , —X (R ₁₁ ), Br, F, I, Cl or NHCOR ₆ , wherein C _1-5 alkoxy is substituted with OH, methoxy or halogen. R ₆ independently represents hydrogen or C _1-4 alkyl; R ₇ independently represents hydrogen or C _1-6 alkyl or (CH ₂ ) nAr; R ₈ represents hydrogen, R ₁₁ , C
Represents OOH, PO ₃ H ₂ , P (O) (OH) R ₇ or tetrazole; R ₉ is C _1-10 alkyl, C _2-10 alkenyl or phenyl, all of which are one or more OH, N (R ₆ ) ₂ , COOH, halogen or XC _1-5
R ₁₀ is R ₃ or R ₄ ; R ₁₁ is C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, which are all 1 or it May be substituted with the above OH, CH ₂ OH, N (R ₆ ) ₂ or halogen; X is (CH ₂ ) n, O, N
R ₆ or S (O) _q ; Y is CH ₃ or —CH ₂ X
(CH ₂ ) nAr; Ar is

[0185]

[Chemical formula 63]

Naphthyl, indolyl, pyridyl or thienyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidylyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperazinyl, piperidinyl, piperidinyl, piperazinyl, piperazinyl Can be substituted with one or more R ₃ or R ₄ groups; A is C═O or [C (R ₆ ) ₂ ] m; B
Is —CH ₂ — or —O—; Z ₁ and Z ₂ are each independently hydrogen, C _1-8 alkyl, C _2-8 alkenyl, C
_2-8 alkynyl, OH, C _1-8 alkoxy, S (O) _q C _1-8
Alkyl, N (R ₆ ) ₂ , Br, F, I, Cl, NHCOR
_{6, -X (CH 2) nR} 8, phenyl, benzyl or C _3-6
Represents cycloalkyl, wherein C _1-8 alkyl, C
_2-8 alkenyl, C _2-8 alkynyl is COOH, OH, C
O (CH ₂ ) nCH ₃ , CO (CH ₂ ) nCH ₂ N (R ₆ ) ₂ or halogen can be substituted; or, Z ₁ and Z ₂ are bonded together by adjacent carbon atoms. -O-
It is also possible to form the A-O-; Z ₃ is Z ₁ or X
R ₉ Y; q is 0, 1 or 2; n is an integer from 0 to 6; m is 1, 2 or 3; a dotted line indicates a possible double bond; or these A pharmaceutically acceptable salt of, having the following limitations. R ₂ is not hydrogen when X is S (O) _q ; only one R ₁₀ is present and P ₁ is absent when a double bond is present; the compound of formula I is (1RS) -1,3 -Diphenylindene-2-carboxylic acid; (cis, cis)-(1RS, 3SR)
-1,3-diphenylindan-2-carboxylic acid; (1RS)
-3- [3-Methyl-1-phenyl- (1H) -indo-2-en-1-yl] propionic acid; or (1RS) -2- [1,3-diphenyl- (1H) -indo-2 -En-1-yl] Not ethanoic acid. A compound represented by or a pharmaceutically acceptable salt thereof. Specifically, the compounds shown in the examples in WO93 / 08799 or their pharmaceutically acceptable salts are used.

[0187] [WO93 / 21219] formula [O] ^{AA 1 -AA 2 -AA 3 -AA 4} -AA 5 -AA 6 [O] (wherein AA ¹ is

[0188]

[Chemical 64]

Wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
Aryl, heteroaryl, fluorenylmethyl methyl, -N (R ³⁾ R ² (wherein R ² and R ³ are each the same or different, each represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl , Arylalkyl, heteroaryl or fluorenylmethyl), COOR ² (wherein R ² is as defined above) —OR ² (wherein R ² is as defined above) —NR ^2- C (O) NR ² R ³ (wherein R ² and R ³ are as defined above) —COC (R ⁹ ) ₃ (wherein R ⁹ is F, Cl, Br or I) --CH ₂ --OR ² (wherein R ² is as defined above) --N (R ^2a )-C (O) OR ³ (wherein R ^2a and R ³ are R ³ except in the case of hydrogen is as defined above) or COR ² ( Among, R ² is as a is) R ¹ defined above is hydrogen or alkyl, Z is -O-, -S (O) m- (wherein m is 0 or an integer of 1 or 2) , -NR ^2- (wherein R ² is as defined above)-(CH ₂ ) n- (where n is zero or an integer of 1, 2, 3 or 4),-( _{CH 2) n-CH = CH-} (CH 2) n- ( wherein, n is as defined above), - CO-, -C (oR 2) R 1 - ( wherein, R ¹ and R ² is as defined above), or —R ² CR ³ —, wherein R ² and R ³ are each the same or different and are each as defined above, X and Y Are the same and are substituted at the same position on the aromatic ring, each being 1, 2, 3 or 4 substituents selected from the following group: Hydrogen, halogen, alkyl, COOR ² (in the formula,
R ² is as defined above, —CON (R ² ) R ³ (wherein R ² and R ³ are as defined above), —N (R ³ ) R ² (wherein , R ² and R ³ are as defined above), or nitro, or

[0190]

[Chemical 65]

(Wherein R, Z, X and Y are as defined above). AA ² is

[0192]

[Chemical formula 66]

(Wherein R ⁴ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, —N (R ^2b ) R ^3b (wherein R ^2b and R ^3b are the same or different, each hydrogen, alkyl, cycloalkyl, aryl or heteroaryl), in -OR ^2b (wherein, R ^2b are as defined ^{above), -CON (R 2b) R} 3b ( wherein, R ^2b And R ^3b are the same or different and are as defined above), —COR ^2b (wherein R ^2b is as defined above), —NH—C (NH) —NH—R ^2b (Wherein R ^2b is as defined above), —COOR ^2b (wherein R ^2b is as defined above), R ¹ and n are as defined above, AA ² Is absent; AA ³ is

[0194]

[Chemical formula 67]

(Wherein R ⁵ is hydrogen, alkyl, aryl, heteroaryl, —CON (R ^2b ) R ^3b (wherein R ^2b and R ^3b are the same or different and are as defined above). ), -COR ^2b (wherein R ^2b is as defined above), -COOR ^2b (wherein R ^2b is as defined above), R ¹ and n are as defined above. AA ³ is absent; AA ⁴ and AA ⁵ are each independently absent or each independently

[0196]

[Chemical 68]

Wherein R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl, R ¹ and n are as defined above, AA ⁶ is

[0198]

[Chemical 69]

(Wherein R ⁷ is aryl or heteroaryl, R ⁸ is —COOR ¹ (wherein R ¹ is as defined above), —OR ¹ (wherein R ¹ is as defined above) --C (O) N (R ¹ ) R ¹ (wherein R ¹ is as defined above) --CH ₂ --OR ¹ (wherein R ¹ is as defined above) R ¹ and n are as defined above; AA ¹ , A
The stereoisomerism of C * in A ² , AA ³ , AA ⁴ or AA ⁵ is D, L or DL, and the stereoisomerism of C * in AA ⁶ is L; or a pharmacologically acceptable salt thereof.
Specifically, the compounds shown in the examples in WO93 / 21219 or pharmaceutically acceptable salts thereof are used.

[WO93 / 13218] Formula [P] XA-Trp-B-Gly-Thr-E-GY (P) {In the formula, A represents Asn or Asp, and B represents His.
Or Lys, E represents Ala or Ser, G represents Ala or Pro, and X represents X ¹ -Gl.
y or

[0201]

[Chemical 70]

And Y is hydroxy, lower alkoxy, amino,

[0203]

[Chemical 71]

Or

[0205]

[Chemical 72]

[Wherein X ¹ and X ³ represent hydrogen, benzyloxycarbonyl, t-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or a carbonyl-substituted or unsubstituted lower alkanoyl, and X ² And Y ² represents hydrogen, Y ¹ represents hydroxy, lower alkoxy or amino, or X
¹ , Y ¹ and X ² , Y ² together are X ¹ -Y ¹
And X ² -Y ² represent a single bond, Z is hydroxy, lower alkoxy, benzyloxy, or benzhydryloxy, Gly-Z ¹ (in the formula, Z ¹ is hydroxy, lower alkoxy, benzyloxy, or benzhidyl. Represents a drilloxy or, together with X ¹ , X ¹ -Z ¹ represents a single bond), Ala-Z ¹ (in the formula, Z ¹ is as defined above), Val-Z ¹ (in the formula: , Z ¹ is as defined above),
Trp-Z ¹ (wherein Z ¹ has the same meaning as above), Trp
-Gly-Z ¹ (wherein Z ¹ has the same meaning as above), Tr
p-Asn-Tyr-Tyr-Trp-Z ¹ (in the formula, Z ¹
Is as defined above), Trp-Phe-Phe-As
n-Tyr-Tyr-7Hyt-Z ¹ (wherein Z ¹ is as defined above, 7Hyt represents 7-hydroxytryptophan), Trp-Ile-Ile-Trp-Z
¹ (in the formula, Z ¹ has the same meaning as above), Trp-Val-
Tyr-Phe-W-His-Leu-Asp-Ile
-Ile-Trp-Z ¹ (wherein Z ¹ has the same meaning as above, W represents Ala, Ser or Cys), Tr
p-W-His-Leu-Asp-Ile-Ile-T
rp-Z ¹ (wherein Z ¹ and W have the same meanings as described above),
Trp-Val-Tyr-Tyr-W-His-Leu
-Asp-Ile-Ile-Trp-Z ¹ (wherein Z ¹ and W have the same meanings as described above), Trp-Leu-Tyr.
-Phe-W-His-Gln-Asp-Val-Il
e-Trp-Z ¹ (wherein Z ¹ and W are as defined above), Trp-Val-Tyr-Phe-W-Phe-
Phe-Asn-Tyr-Tyr-Trp-Z ¹ (wherein
Z ¹ and W are as defined above, and Trp-Phe-
Phe-Asn-Tyr-Tyr-W-His-Leu
-Asp-Ile-Ile-Trp-Z ¹ (wherein Z ¹ and W have the same meanings as described above), Trp-Phe-Phe
-Asn-Tyr-Tyr-Asn-Ile-Ile-
Trp-Z ¹ (in the formula, Z ¹ has the same meaning as above), or J-Phe-M-Q-Tyr-R-T-Z ¹ (in the formula, J
Is Trp or single bond, M is Phe or single bond, Q is Asn or single bond, R is Tyr or single bond, T is T
rp, Ala, Phe, Tyr, Trp-Trp, As
n-Tyr-Tyr-Trp, Trp-Asn-Tyr
-Tyr-Trp, Trp-Val-Tyr-Phe-
W-His-Leu-Asp-Ile-Ile-Trp
(Wherein W has the same meaning as defined above) or represents a single bond, and at least two of J, M, Q, R and T do not simultaneously represent a single bond, and Z ¹ has the same meaning as defined above. A)]} or a pharmacologically acceptable salt thereof. Specifically, the compounds shown in Examples in WO93 / 13218 or pharmaceutically acceptable salts thereof are used.

[EP-0555537A2] [Q] peptide derivative

[0208]

[Chemical formula 73]

(Wherein A is a group of the formula R ¹¹ O—CO— (wherein R ¹¹ is a lower alkyl group or a phenyl group), or a group of the formula R ¹²
R ¹³ N—C (═O) — (wherein R ¹² is a lower alkyl group, a cycloalkyl group, a 1-adamantyl group, or 1 of its benzene ring.
Or a desired hydrogen atom of 2 is independently a phenyl group which may be substituted with a halogen element, a trifluoromethyl group, a nitro group, an amino group or a formylamino group, a pyridyl group or a thienyl group, and R ¹³ is hydrogen. An atom, a lower alkyl group or a cycloalkyl group, or R ¹² and R ¹³ together with their adjacent nitrogen atoms are 5 to 9 membered and 4 to
A nitrogen-containing saturated heterocycle having 8 carbon atoms, wherein in the methylene group forming the ring, one desired methylene group not adjacent to the above nitrogen atom is changed to a thio group. Wherein 1 to 4 hydrogen atoms of the carbon atoms of the heterocycle can each independently be changed to a lower alkyl group, and two adjacent carbon atoms of the heterocycle form a benzofused ring. B is an oxygen atom or a formula —NR ² group (wherein R ² is a hydrogen atom or a lower alkyl group), R ³ is a lower alkyl group, a cycloalkyl group, an aryl group, a heterocyclic group, A cycloalkyl lower alkyl group, an aryl lower alkyl group or a heterocyclic lower alkyl group, X ¹ is an oxygen atom or a formula —NR ⁴ group (in the formula, R
⁴ is a hydrogen atom or a lower alkyl group), and R ⁵ is 3-
An indolylmethyl, 3-benzothienylmethyl, 1-naphthylmethyl or benzyl group, wherein 1 on the ring
Alternatively, 2 desired hydrogen atoms are substituted with a hydroxyl group, a halogen group, a formyl group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkoxycarbonyl group, or a nitro group. Or a compound represented by the formula R ⁵¹ —CO—X ² (wherein R ⁵¹ is a lower alkyl group, a lower alkoxy group, or an amino group which may be substituted with a lower alkyl group, and X ² is an oxygen atom). Or formula-N
R ⁵² — (wherein R ⁵² is a hydrogen atom or a lower alkyl group)
And X ³ is an oxygen atom or a sulfur atom, and R ⁶ may have a hydrogen atom or a substituent selected from the group consisting of a hydroxyl group, a lower alkoxy group, a lower alkylthio group and a heterocyclic group. A lower alkyl or lower alkenyl group, n is 0 or 1, Y is a hydroxymethyl group, a formula CO ₂ R ⁷¹ (wherein R ⁷¹ is a hydrogen atom or a lower alkyl group), a formula CONHR ⁷² (wherein R ⁷² Is a hydrogen atom, or a lower alkyl group optionally having a substituent selected from the group consisting of a hydroxyl group, a carboxyl group and a sulfo group), a 1H-tetrazol-5-yl group, a sulfo group and a phosphono group, or These pharmacologically acceptable salts. Specifically, EP-0555537
The compound shown in the example in A2 or a pharmaceutically acceptable salt thereof is used.

[JP-A-5-178890] Formula [R]

[0211]

[Chemical 74]

[Wherein R ¹ is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aralkyl group, an aryl group, a 5- to 10-membered heterocyclic group or a 5- to 10-membered heterocyclic lower alkyl group ( The lower alkyl group, cycloalkyl group, cycloalkyl lower alkyl group, aralkyl group, aryl group, 5- to 10-membered heterocyclic group and 5- to 10-membered heterocyclic lower alkyl group are each independently on their chain. And / or a lower alkyl group on the ring, a halogen atom,
Hydroxyl group, lower alkoxy group, nitro group, trifluoromethyl group, cyano group, formyl group, lower alkanoyl group,
Carboxyl group, lower alkoxycarbonyl group, amino group, mono-lower alkylamino group, di-lower alkylamino group, formylamino group, alkanoylamino group, aroylamino group, carbamoyl group, N-mono-lower alkylcarbamoyl group or N, N-di Lower alkylcarbamoyl group, mercapto group, lower alkylthio group or lower alkanoylthio group may be present); p is 0 to 2
R ¹ is a single bond or a divalent lower alkylene group optionally substituted with a lower alkyl group; R ²
Is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aralkyl group, an aryl group, 5 to 10
Membered heterocyclic group or a 5- to 10-membered heterocyclic lower alkyl group; X ¹ is an oxygen atom or a formula: —NR ³ — [wherein R ³ represents a hydrogen atom or a lower alkyl group] R ⁴ is a 5- to 10-membered heterocyclic lower alkyl group [said 5 to
The 10-membered heterocyclic lower alkyl group is a lower alkyl on the ring or has the formula: R ⁴¹ —CO— (CH ₂ ) _q — (wherein R ⁴¹ is a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, Aralkyloxy group, amino group, mono-lower alkylamino group or di-lower alkylamino group; q is 0 to
A group represented by the formula 6)] or an aryl lower alkyl group [wherein the aryl lower alkyl group has a nitro group on its ring, a compound represented by the formula: R ⁴² —CO— (CH ₂ ). _r
-(In the formula, R ⁴² is a lower alkyl group, a lower alkoxy group,
A group represented by an amino group, a mono-lower alkylamino group or a di-lower alkylamino group, and r represents an integer of 0 to 6, a compound represented by the formula: R ⁴² —COX ² — (wherein R ⁴² is as defined above). Has the meaning, X ² is an oxygen atom or the formula: —NR ⁴³ — (wherein R 2
⁴³ group or the formula is represented by a hydrogen atom or a lower alkyl _{^{group): R 44 O- (CH 2}} ) s - ( wherein, R ⁴⁴ represents a hydrogen atom or a lower alkyl group, s is 0 to 6 Represents an integer)
May have a group represented by]; X ³ represents an oxygen atom or a sulfur atom; A ² represents the following general formula [RII]
An arbitrary group selected from the group consisting of groups represented by [RVII] is shown.

[0213]

[Chemical 75]

[Wherein Y is a hydroxy lower alkyl group,
Sulfo group, phosphono group, formula: —CO ₂ R ⁸¹ (in the formula, R ⁸¹
Represents a hydrogen atom or a carboxy protecting group) or a formula: —CONR ⁸² R ⁸³ (wherein R ⁸² and R ⁸³ are each independently a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group, a benzene ring) R represents a group represented by any of the above 1 to 5 hydrogen atoms independently represents a lower alkyl group or a phenylsulfonyl group optionally substituted with a halogen atom or a carboxy lower alkyl group; R
⁵¹ represents a hydrogen atom or a lower alkyl group, or R
Together with ⁶¹ represents a methylene group; R ⁵³ , R ⁶¹ and R
⁶² are each independently a hydrogen atom, a lower alkyl group, a lower alkenyl group, an aryl group, an aryl lower alkyl group, 5
10-membered heterocyclic group or 5- to 10-membered heterocyclic lower alkyl group (the lower alkyl group, lower alkenyl group, aryl group, aryl lower alkyl group, 5- to 10-membered heterocyclic group and heterocyclic lower alkyl group) Are each independently a hydroxyl group, a lower alkyl group, a halogen atom, a lower alkoxy group, an aryloxy group, an acyloxy group, a carboxyl group, a protected carboxyl group on their chain and / or ring.
Having an amino group, monoalkylamino group, di-lower alkylamino group, carbamoyl group, N-mono-lower alkylcarbamoyl group, N, N-di-lower alkylamino group, lower alkoxycarbonylamino group or aryloxycarbonylamino group R ⁶¹ is R ⁵¹
And R ⁶² may represent a methylene group together with R ⁵² below (provided that when R ⁵¹ represents a lower alkyl group, R ⁶¹ represents a hydrogen atom other than hydrogen atom). When R ⁵² represents a group other than a hydrogen atom,
R ⁶² represents a hydrogen atom or a lower alkyl group); R ⁵² represents a hydrogen atom, an aryl group, an aralkyl group, a carboxyl group,
Carbamoyl, N- mono-lower alkylcarbamoyl group, N, N- di-lower alkylcarbamoyl group or N- arylcarbamoyl or shown, or represents a single bond together with R ^7; R ⁷ is a hydrogen atom, Represents a lower alkyl group, a lower alkoxy group, a hydroxyl group, or, together with R ⁵² , represents a single bond, t represents an integer of 2 to 6; Z represents C
H or N is shown; v is an integer of 1 to 3]} or a pharmaceutically acceptable salt thereof. Specifically, the compounds shown in Examples in JP-A-5-178890 or pharmaceutically acceptable salts thereof are used.

[0215]

[Chemical 76]

The compound represented by or a pharmaceutically acceptable salt thereof is preferably used.

[0217] [Patent 5-279390] Formula [S] _{cyclo (-Dtrp (COOCH 3) -DAsp} -Pro-DtertLe u-γMeLeu-) cyclic pentapeptide and its analogous compound represented by [S] or a A pharmaceutically acceptable salt.

[EP-0558258 A1] Formula [T]

[0219]

[Chemical 77]

Wherein ^{one of} X and Y is N and the other is O; R is naphthyl or R ¹ , R ² and R ³
Naphthyl substituted with R ¹ , R ² and R ³
Are independently hydrogen; alkyl, alkenyl, alkynyl,
Alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, all of which are Z ¹ , Z ²
And Z ³ ; halo; hydroxyl; cyano; nitro; -C
(O) H; -C (O) R ⁶ ; CO ₂ H; CO ₂ R ⁶ ; -SH; -S
^{(O) nR 6; -S (} O) m-OH; -S (O) m-OR 6; -OS (O)
^{m-R 6; -OS (O} ) m-OH; -OS (O) m-OR 6; -Z 4 -N
R ⁷ R ⁸ ; or -Z ⁴ -N (R ¹¹ ) -Z ⁵ -NR ⁹ R ¹⁰ may be substituted; R ⁴ and R ⁵ are independently hydrogen; alkyl, alkenyl, alkynyl, alkoxy, Cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, all of which are Z ¹ , Z ² and Z ³ ; halo; hydroxyl; cyano; nitro; --C (O) H; O) R ⁶ ;
CO ₂ H; CO ₂ R ⁶ ; -SH; -S (O) nR ⁶ ; -S (O) m-O
H; -S (O) m- OR 6; -OS (O) m-R 6; -OS (O) m-O
H; -OS (O) m-OR ⁶ ; -Z ⁴ -NR ⁷ R ⁸ ; or -Z ⁴ -N
(R ^{1 1} ) -Z ⁵ —NR ⁹ R ¹⁰ may be substituted; or R ⁴ and R ⁵ may be joined together to form an alkylene or alkenylene, any of which may be Z ¹ , Z ² or Z. Optionally substituted with ³ ), which complete a 4-8 membered saturated, unsaturated or aromatic ring with adjacent carbon atoms; R ⁶ is alkyl, alkenyl , Alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z ¹ , Z ² or Z ³ ; R ⁷ Is defined as R ⁶ , or hydrogen, hydroxyl, cyano, —C (O) H, —C (O) R ⁶ , CO
₂ R ⁶ ; or when Z is not SOn, R ⁷ is —SH, CO
R ⁶ , -S (O) m-OH, -S (O) m-OR ⁶ , -OS (O) m-
R ⁶ , —OS (O) m—OH or —OS (O) m—OR ⁶ ; R ⁸ is R ⁶
Or hydrogen, or when Z ⁴ is not CO and R ⁷ is not COH, —C (O) R ⁶ or CO ₂ R ^6, R ⁸ is COH, —C (O) R ⁶ ; Or NR ⁷ R ⁸ is alkylene or alkenylene (Z ¹ , Z ² or Z respectively)
Optionally substituted with ³ ) to form a saturated, unsaturated or aromatic 3-8 membered ring; R ⁹ is as defined for R ⁶ or hydrogen, hydroxyl, —C (O) H , -C (O) R
⁶ , CO ₂ R ⁶ ; -SH, SOnR ⁶ , -S (O) m-OH, -S
(O) m-OR ⁶ , -OS (O) m-R ⁶ , -OS (O) m-OH or-
OS (O) m-OR ⁶ ; R ¹⁰ is as defined for R ⁶ , or hydrogen, or Z ⁵ is not CO, R ⁹ is COH, —C
(O) When R ⁶ or CO ₂ R ⁶ is not R ¹⁰ is COH or-
Can be C (O) R ⁶ ; R ¹¹ is as defined for R ⁶ or is hydrogen, hydroxyl, —C (O) H, —C
(O) R ⁶ or CO ₂ R ⁶ , or _{two of} R ⁹ , R ¹⁰ and R ¹¹ are alkylene or alkenylene (optionally substituted with Z ¹ , Z ² or Z ³ respectively) Form a saturated, unsaturated or aromatic 3-8 membered ring with adjacent atoms; Z ¹ , Z ² and Z ³ are H, halogen, hydroxyl, alkyl, alkenyl, aralkyl, alkoxy, aryloxy, Aralkyloxy, -SH, -S (O) nZ ⁶ , -S (O) m-OH, -S (O) m-O
Z ⁶ , -OS (O) m-OH, -OS (O) m-OZ ⁶ , oxo, cyano, nitro, -C (O) H, -C (O) Z ⁶ , CO ₂ H, CO
₂ Z ⁶ , Z ⁴ NZ ⁷ Z ⁸ , Z ⁴ NZ ¹¹ Z ⁵ Z ⁶ , Z ⁴ NZ ¹¹ Z ⁵ N
Z ⁷ Z ⁸ ; Z ⁴ and Z ⁵ are vinyl bonds, Z ⁹ SOnZ ¹⁰ and Z ⁹ C
OZ ¹⁰ , Z ⁹ CSZ ¹⁰ , Z ⁹ OZ ¹⁰ , Z ⁹ SZ ¹⁰ or Z ⁹
OCOZ ¹⁰ ; Z ⁶ , Z ⁷ and Z ⁸ are H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl; or NZ ⁷ Z ⁸ is saturated with alkylene or alkenylene, Form an unsaturated or aromatic 3- to 8-membered ring; Z ⁹ , Z ¹⁰ are single bonds, alkylene, alkenylene or alkynylene; Z ¹¹ is as defined for R ⁶ or hydrogen, hydroxyl, --C
(O) H, -C (O) Z ⁶ or CO ₂ Z ⁶ ; Z ⁷ , Z ⁸ and Z
Two of ¹¹ are alkylene or alkenylene, which are saturated, unsaturated or aromatic with the atoms to which they are adjacent 3 to 3
A 8-membered ring is formed; m = 1 to 2; n = 0, 1 or 2; a compound or a pharmaceutically acceptable salt thereof. Specifically, the compounds shown in the examples in EP-0558258 A1 or pharmaceutically acceptable salts thereof are used.

[0221]

[Chemical 78]

A compound which is or a pharmaceutically acceptable salt thereof is preferably used.

[WO93 / 23404] Formula [U]

[0224]

[Chemical 79]

Wherein Ar is a substituted or unsubstituted aromatic or heterocyclic ring; R is H or a substituted or unsubstituted straight chain, branched chain, cyclic or straight chain, branched chain, cyclic mixture. Is an alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxyalkyl or alkoxycarbonyl group having 1 to 20 carbon atoms; A is a functional group having a polar group, preferably CO
OH or RNH; R ₁ is R, R—C═O, R substituted with one or more heteroatoms, a substituted or unsubstituted aryl group, or aryl (CH ₂ ) n; R ₂ Is (CH ₂ ) n, CHR, C (R) ₂ , COO, OC
O, NHCO, CONH, SO, SO ₂ or NR; R ₃
And R ₄ are the same or different or absent and each is ═O, hydrogen, O-aryl, OR, O-alkyl or alkyl, aryl, SR, S-aryl, N
HR, NH-aryl, NR, or another heteroaromatic group; R ₅ is H, OH or R; E and F are the same or different and are N or (CH ₂ ) p; p is zero. Is an integer between 5 or 0; m and n are zero and 1
Is an integer between 0 or 0; T is O, S, NCOR
Or NR; U and V are the same or different and are (CH ₂ ) n; W is CO, (CH ₂ ) n, (CH ₂ ) n
-CHR or CHR- (CH ₂₎ be n; X and Y
Are the same or different and H, alkyl or aryl, or X and Y form a saturated or unsaturated mono- or heterocyclic ring of 3 to 15 members; Z is H, SR, NHR or N (R) ₂ . , A compound or a pharmaceutically acceptable salt thereof. Specifically, the compounds shown in the examples in WO 93/23404 or pharmaceutically acceptable salts thereof are used.

[0226]

[Chemical 80]

Compounds of are preferably used.

[EP-569193-A1] Formula [V]

[0229]

[Chemical 81]

Wherein _{one of} X and Y is N and the other is O; R ₁ , R ₂ and R ₃ are independently hydrogen (R ₁ is not hydrogen); alkyl, alkenyl, alkynyl , Alkoxy, cycloalkyl (alkyl), cycloalkenyl (alkyl), aryl, aryloxy, aralkyl or aralkoxy; halo, OH, CN, NO ₂ ,
CHO, COR ₆ , CO ₂ H, CO ₂ R ₆ , -SH, -S (O)
nR ₆ , -S (O) m-OH, -S (O) m-OR ₆ , -OS (O) m-R
₆ , -OS (O) m-OH, -OS (O) m-OR ₆ , -Z ₄ -NR ₇ R
₈ or -Z ₄ -N (R ₁₁ ) -Z ₅ -NR ₉ R ₁₀ and R ₄ and R ₅ are the same as defined for R _{1 to} R ₃ or are bonded together to form 4 to Form an 8-membered saturated, unsaturated or aromatic ring; R ₄ is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,
Cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, all of which may be substituted with Z ₁ , Z ₂ and Z ₃ ; R ₇ is hydrogen; alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cyclo Alkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, all of which may be substituted with Z ₁ , Z ₂ and Z ₃ ; CN; OH; CHO, COR ₆ ; CO ₂
H, CO ₂ R ₆ ; -SH, when Z ₄ is not -S (O) m-
_{-S (O) nR 6, -S} (O) m-OH, -S (O) m-OR 6 or -
OS (O) m-OR ₆ ; R ₈ is hydrogen; when Z ₄ is not —C (O) — and R ₇ is not CHO, COR ₆ , CO ₂ H, CO ₂ R _6, CHO, COR ₆ ; alkyl , Alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, all of which are Z
¹ , Z ² and Z ³ may be substituted; or R ₇ and R ₈ are adjacent to each other by alkylene or alkenylene, which may be substituted by Z ¹ , Z ² or Z ³ , respectively. Form a saturated, unsaturated or aromatic 3-8 membered ring with the atoms present; R ₉ is hydrogen; hydroxyl;
CHO, COR ₆ ; CO ₂ H, CO ₂ R ₆ ; -SH, -S (O)
nR ₆ , -S (O) m-OH, -S (O) m-OR ₆ , -OS (O) m-R
₆ , -OS (O) m-OH or -OS (O) m-OR ₆ ; alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, which are Either can be substituted with Z ₁ , Z ₂ and Z ₃ ; R ₁₀ is hydrogen; Z ₅ is not —C (O) — and R ₉ is CHO, COR ₆ , CO ₂ H, CO ₂ When it is not R _6, it is CHO, COR ₆ ; alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, all of which are Z
¹ , R 2 can be substituted with Z ² and Z ³ ; R ₁₁ is hydrogen; one of R ₉ and R ₁₀ is hydroxyl, CO ₂ H,
Hydroxyl, CO ₂ H or CO _{2 when not} CO ₂ R ₆
R ₆ ; CHO, COR ₆ ; alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, all of which are Z
₁ , Z ₂ and Z ₃ may be substituted; or any two of R ₉ , R ₁₀ and R _{11 taken} together are alkylene or alkenylene (substituted by Z ₁ , Z ₂ or Z ₃ respectively). Optionally form a saturated, unsaturated or aromatic 3-8 membered ring with the adjacent atoms; Z ₁ , Z ₂ and Z ₃ are each independently H, halogen, hydroxyl, Alkoxy, -SH, -S (O) nZ ₆ ,
-S (O) m-OH, -S (O) m-OZ 6, -OS (O) m-OH or ^{-OS (O) m-OZ 6} ; oxo, cyano, nitro, -C
(O) H, -C (O) Z ₆ , CO ₂ H, CO ₂ Z ₆ , NZ ₇ Z ₈ ,
^{-C (O) NZ 7 Z 8} ; or ^{-S (O) mZ 7 Z 8} ; Z 4 and Z ₆ are each independently a single bond, -SOn-, CO, CS
Or Z ¹⁰ , Z ⁹ OZ ¹⁰ , Z ⁹ SZ ¹⁰ or Z ⁹ OCOZ
¹⁰ ; alkyl, alkenyl, alkynyl, alkoxy,
Cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, all of which may be substituted with Z ₁ , Z ₂ and Z ₃ ; any of R ₉ , R ₁₀ and R ₁₁ . Or two taken together are alkylene or alkenylene (which may be respectively substituted by Z ₁ , Z ₂ or Z ₃ ) Z ₆ , Z ₇ and Z ₈ are each independently H, alkyl, alkenyl, alkynyl, alkoxy , Cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, or Z ₇ and Z ₈ together are alkylene or alkenylene, with 3 to 8 membered saturated with adjacent nitrogen atoms,
Form an unsaturated or aromatic 3- to 8-membered ring; m = 1 to
2; n = 0, 1 or 2; a compound which is a phenylsulfonamide derivative, or a pharmaceutically acceptable salt thereof. Specifically, the compounds shown in Examples in EP-569193-A1 or pharmaceutically acceptable salts thereof are used.

[0231]

[Chemical formula 82]

Compounds which are: are preferably used.

[WO-9317701-A1] Formula [W1], [W2] or [W3]

[0234]

[Chemical 83]

X is an α-amino acid having a sterically constrained 4-16C side chain, Y is Ser and Z is an α-amino acid having a sterically constrained side chain. This side chain is a compound or a compound thereof in which the C-amino and N-amino groups of X are cyclic pentapeptides which form 1 to 3 separate or fused rings having an amino group which is one member of the ring. A pharmaceutically acceptable salt. Specifically, WO-9
The compound shown in the examples in 317701-A1 or a pharmaceutically acceptable salt thereof is used.

[Bioorganic & Medicinal Chemistry Let
ters, Vol.3, No.10, pp.2099-2104,1993] Formula [X1], [X2] or [X3]

[0237]

[Chemical 84]

A compound or a pharmaceutically acceptable salt thereof, which is a compound of: Specifically, WO-9317701-A
The compounds shown in the examples in 1 or pharmaceutically acceptable salts thereof are used.

The compound having an endothelin receptor antagonistic activity according to the present invention can be used for the prevention and / or treatment of functional deterioration of various organs and its complications that occur during or after surgery or transplantation of organs. Examples of organs include liver, kidney, heart, spleen, pancreas and the like. For example, at the time of liver surgery, a method of temporarily tying a hepatic blood vessel and then performing reperfusion after the operation is generally used. However, if the ligation is performed for a long time (5 to 10 minutes or more), the liver function after reperfusion is increased. Is known to decrease, resulting in liver failure. As a model for this, the effect of a compound having an endothelin receptor antagonistic action was examined using a rat ischemia-reperfusion liver injury model, and the compound was found to have a prominent action for improving a state of hepatic dysfunction. Therefore, the compound having an endothelin receptor antagonism is effectively used for preventing or (and) treating the functional deterioration of the organ or (or) the complication thereof during or after the surgery or transplant of the organ such as the liver. be able to. The compound having an endothelin receptor antagonistic activity used in the present invention is a safe and low toxic compound. Examples of liver function deterioration occurring during or after liver surgery or transplantation or indicators thereof include transaminase (GPT / G).
OT) activity, decreased production of fibrinogen or prothrombin, decreased production of heparin, etc.,
A compound having an endothelin receptor antagonistic effect has a prophylactic or / and therapeutic effect on these hypofunctions of the liver and its complications. When a compound having an endothelin receptor antagonism is used for preventing or / and treating organ functional decline and its complications occurring during or after organ surgery or transplantation, the compound is used in a warm-blooded mammal (for example, rabbit). , Dogs, cats, rats, mice, monkeys, cows, humans, etc.), for example, orally or parenterally. The dosage form of the preparation may be either an oral preparation (eg powder, tablets, granules, capsules) or a parenteral preparation (eg suppositories, injections). These preparations can be prepared by a method known per se. When administered parenterally, it is usually administered in the form of a solution (eg, injection). The single dose varies depending on the administration subject, target organ, symptom, administration method, etc .;
It is convenient to administer about mg, preferably about 0.01 to 50 mg, more preferably about 0.01 to 20 mg by intravenous injection. Part 1 when administered orally
The dose is usually about 5 mg to 1 g, preferably about 10 to 100 mg per kg body weight before surgery. The injections include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drip injections and the like. Such an injection is prepared by a method known per se, that is, by dissolving, suspending or emulsifying a compound having an endothelin receptor antagonistic action in a sterile aqueous or oily liquid. Aqueous solutions for injection include physiological saline, isotonic solutions containing glucose and other adjuvants (eg, D-sorbitol, D-
Mannitol, sodium chloride, etc.)
It may be used in combination with a suitable solubilizing agent such as alcohol (eg ethanol), polyalcohol (eg propylene glycol, polyethylene glycol), nonionic surfactant (eg polysorbate 80, HCO-50) and the like. Examples of the oily liquid include sesame oil and soybean oil, which may be used in combination with solubilizing agents such as benzyl benzoate and benzyl alcohol. In addition, a buffer (for example, phosphate buffer, sodium acetate buffer),
It may be mixed with soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), preservatives (eg, benzyl alcohol, phenol, etc.). The adjusted injection solution is usually filled in a suitable ampoule. When manufacturing an oral preparation such as a powder, a tablet, a granule and a capsule, a pharmaceutically acceptable carrier can be added. As the carrier, an excipient (for example,
Lactose, starch etc.), lubricants (eg magnesium stearate, talc etc.), binders (hydroxypropyl cellulose, hydroxypropylmethyl cellulose, macro gold etc.), disintegrants (eg starch, carboxymethyl cellulose calcium etc.) etc. Used. In addition, if necessary, a preservative (for example,
Additives such as benzyl alcohol, chlorobutanol, methyl paraoxybenzoate, propyl paraoxybenzoate, etc.), antioxidants, colorants, sweeteners and the like can be used. The preparation containing the compound having an endothelin receptor antagonistic activity of the present invention can be effectively used for the prevention and / or treatment of organ functional decline that occurs during surgery or transplantation of organs.

[0240]

EXAMPLES The present invention will be described in more detail below with reference to examples and formulation examples, but these do not limit the scope of the present invention. The compound 1 represented by the formula Cyclo (-D-Asp-Asp (R1) -Asp-D-Thg (2) -Leu-D-Trp-) used in the following Examples and Preparation Examples is the compound described in EP -A-0,528,3
The compound described in 12 above is only a representative example of the compound having an endothelin receptor antagonism used in the present invention, and other compounds having an endothelin receptor antagonism can be similarly used. In addition to Formulation Examples 1 to 4, the formulation examples described in the above-mentioned patent application specification in which a compound having an endothelin receptor antagonistic action is disclosed can be similarly used. Example 1 Compound 1 [Cyclo (-D-Asp-Asp (Rl) -Asp-DT
hg (2) -Leu-D-Trp-)] (0.266 mol) was dissolved in methanol (6 L). While stirring under ice-cooling, 0.1N aqueous sodium hydroxide solution (5.41 L) was added to this solution over 3 hours and 25 minutes. Methanol was distilled off from the reaction solution under reduced pressure. Pure water (5 L) was added to the residual liquid, and the mixture was washed twice with ethyl acetate (5 L). The aqueous layer was concentrated under reduced pressure to 11341 g. Remaining liquid is Diaion HP-20 (15 L,
It was adsorbed on a column packed with Mitsubishi Kasei (Japan). After washing the column with pure water (45 L), methanol-pure water (volume ratio 1:
It was eluted in 1). The target fractions were collected and concentrated under reduced pressure to 1265 g. Activated carbon (20 g, white heron P, Takeda Pharmaceutical Co., Ltd., Japan) was added to this residual liquid, and the mixture was stirred at 25 ° C. for 30 minutes. Activated carbon was filtered off with a Millipore filter (0.5 μm, diameter 90 mm, manufactured by Millipore, USA), and the activated carbon was washed with pure water (0.8 L). The filtrate was combined with the washing solution and frozen to obtain a disodium salt of compound 1 (230 g). Elemental analysis _{C 45 H 51 N 9 O 11} SNa 2 · 3.8H 2 O Calculated: C, 51,95; H, 5.68 ; N, 12.12; S, 3.08; Na, 4.42 Found: C, 52,11 H, 6.02; N, 12.16; S, 3.02; Na, 4.62 (Na was measured by atomic absorption spectrophotometry) [Example 2] Rat ischemia-reperfusion liver injury model was prepared by Koo et al. 1) I referred to the method. Male Wistar rats weighing 250 to 300 g, which had been fasted (free drinking water) for 1 day, were used for the experiment. Rats were anesthetized with pentobarbital sodium (60 mg / kg, intraperitoneal administration), and the body temperature was kept at 37 ° C using a heat retaining device. A polyethylene tube for drug administration and venous blood collection was intubated in the left femoral artery, heparin (200 unit / kg, intravenous administration) was administered, and then venous blood (about 1 ml: before ischemia) was collected. Rats were divided into 3 groups (sham operation group, control group, compound 1 group), physiological saline was used for sham operation / control group, and compound 1 2N was used for compound 1 group.
3 mg / kg of salt a was intravenously administered. Dissect the right branch of the portal vein by incising the abdomen and clip it to the right lobe of the liver.
Blood flow to the square leaf was blocked (control group / Compound 1 group). In the sham operation group, the same treatment was performed except for the operation of applying a clip. After blocking the blood flow for 25 minutes, the clip was opened to reopen the blood flow, and 1 hour after that, venous blood was collected again (1 hour after reperfusion). GPT in collected venous blood plasma
-The GOT activity was measured using the UV rate method (GPT-UV Test Wako-GOT-UV Test Wako). A large-scale test between each group was performed using the pre-ischemic value and the 1-hour reperfusion value, and a significance rate of 5% or less was considered significant. The results are shown in [Table 1] and [Table 2]. 1) Koo et al. (1991) Contribution of no-reflow phenomen
on to hepatic injuryafter ischemia-reperfusion: ev
idence for a role for superoxlde anlon.Hepatolog
y ,, 15, 507-514.

[0241]

[Table 1]

[0242]

[Table 2]

The values in the table represent mean ± standard error. The plasma GPT / GOT activity before ischemia was not significantly different among the three groups of the sham operation group, the control group, and the compound 1 group. The GPT activity of the control group 1 hour after reperfusion was significantly higher than that of the sham-operated group. Compound 1 2Na salt 3 mg / kg
GPT activity 1 hour after reperfusion after intravenous administration was similar to that in the sham-operated group. The GOT activity of the control group after 1 hour of reperfusion was also higher than that of the sham-operated group, and the 2Na salt of compound 1 was 3 mg /
The intravenous administration of kg tended to suppress the increase in GOT. From these results, Compound 1 showed a significant inhibitory effect on an increase in plasma GPT value associated with rat ischemia-reperfusion liver injury, and also showed an inhibitory tendency on an increase in plasma GOT value. This suggests the involvement of endogenous endothelin in ischemia-reperfusion liver injury, and that a compound having an endothelin receptor antagonism is a prophylactic / therapeutic drug for this ischemia-reperfusion liver injury. It is shown. [Formulation Example 1] 50 mg of the 2Na salt of the compound 1 used in Example 2 was dissolved in 50 ml of Japanese Pharmacopoeia distilled water for injection.
Japanese Pharmacopoeia distilled water for injection was added to make 100 ml. This solution was filtered under sterile conditions, and then 1 ml of this solution was taken, filled into a vial for injection under sterile conditions, freeze-dried and sealed. [Formulation Example 2] 500 mg of the 2Na salt of Compound 1 used in Example 2 was dissolved in 50 ml of Japanese Pharmacopoeia distilled water for injection, and then Japanese Pharmacopoeia distilled water for injection was added to make 100 ml. This solution was filtered under sterile conditions, and then 1 ml of this solution was taken, filled into a vial for injection under sterile conditions, freeze-dried and sealed. [Formulation Example 3] 5 g of the 2Na salt of Compound 1 used in Example 2 was dissolved in 50 ml of Japanese Pharmacopoeia distilled water for injection, and then Japanese Pharmacopoeia distilled water was added to make 100 ml. This solution was filtered under sterile conditions, and then 1 ml of this solution was taken, filled into a vial for injection under sterile conditions, freeze-dried and sealed. [Pharmaceutical Example 4] 15 g of the 2Na salt of the compound 1 used in Example 2 was dissolved in 50 ml of Japanese Pharmacopoeia distilled water for injection, and then Japanese Pharmacopoeia distilled water was added to make 100 ml. This solution was filtered under sterile conditions, and then 1 ml of this solution was taken, filled into a vial for injection under sterile conditions, freeze-dried and sealed.

[0244]

INDUSTRIAL APPLICABILITY The compound having an antagonistic action on endothelin receptors can be effectively used for the prevention and / or treatment of the functional deterioration of organs which occurs during the surgery or transplantation of organs.

[0245]

[Sequence list]

 SEQ ID NO: 1 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence features Characteristic symbols: disulfide-bonds Location: 1,15 Location: 3,11 Sequence Cys Ser Cys Ser Ser Leu Met Asp Lys Glu Cys Val Tyr Phe Cys His 1 5 10 15 Leu Thr Leu Ile Trp 20.

SEQ ID NO: 2 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence features Characteristic symbols: disulfide-bonds Location: 1,15 Location: 3, 11 Sequence Cys Ser Cys Ser Ser Leu Met Asp Lys Glu Cys Val Tyr Phe Cys His 1 5 10 15 Leu Thr Cha Ile Trp 20.

SEQ ID NO: 3 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence features Characteristic symbols: disulfide-bonds Location: 1,15 Location: 3, 11 Sequence Cys Ser Cys Ser Ser Leu Met Asp Lys Glu Cys Val Tyr Phe Cys His 1 5 10 15 Leu Thr Phe Ile Trp 20.

SEQ ID NO: 4 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence features Characteristic symbols: disulfide-bonds Location: 1,15 Location: 3, 11 Characteristic symbol: modified site Location: 19 Other information: Xaa indicates γLeu. Sequence Cys Ser Cys Ser Ser Leu Met Asp Lys Glu Cys Val Tyr Phe Cys His 1 5 10 15 Leu Thr Xaa Ile Trp 20.

SEQ ID NO: 5 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence features Characteristic symbols: disulfide-bonds Location: 1,15 Location: 3, 11 Sequence Cys Ser Cys Ser Ser Leu Met Asp Lys Glu Cys Val Tyr Phe Cys His 1 5 10 15 Leu Thr Asn Ile Trp 20.

SEQ ID NO: 6 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence characteristics Features symbol: disulfide-bonds Location: 1,15 Location: 3, 11 Sequence Cys Ser Cys Ser Ser Leu Met Asp Lys Glu Cys Val Tyr Phe Cys His 1 5 10 15 Leu Ser Leu Ile Trp 20.

SEQ ID NO: 7 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence features Characteristic symbols: disulfide-bonds Location: 1,15 Location: 3, 11 Sequence Cys Ser Cys Ser Ser Leu Met Asp Lys Glu Cys Val Tyr Phe Cys His 1 5 10 15 Leu Asn Leu Ile Trp 20.

SEQ ID NO: 8 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence features Characteristic symbols: disulfide-bonds Location: 1,15 Location: 3, 11 Sequence Cys Ser Cys Ser Ser Leu Met Asp Lys Glu Cys Val Tyr Phe Cys His 1 5 10 15 Leu Gly Leu Ile Trp 20.

SEQ ID NO: 9 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence characteristics Features symbol: disulfide-bonds Location: 1,15 Location: 3, 11 Sequence Cys Thr Cys Phe Thr Tyr Lys Asp Lys Glu Cys Val Tyr Tyr Cys His 1 5 10 15 Leu Thr Leu Ile Trp 20.

SEQ ID NO: 10 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence features Characteristic symbols: disulfide-bonds Location: 1,15 Location: 3, 11 Sequence Cys Ser Cys Ser Ser Leu Met Asp Ala Glu Cys Val Tyr Phe Cys His 1 5 10 15 Leu Thr Leu Ile Trp 20.

SEQ ID NO: 11 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence characteristics Features symbol: disulfide-bonds Location: 1,15 Location: 3, 11 Characteristic symbol: Position of modified site] 1 Other information: Xaa indicates Mpr. Sequence Mpr Ser Cys Ser Ser Leu Met Asp Lys Glu Cys Val Tyr Phe Cys His 1 5 10 15 Leu Thr Leu Ile Trp 20.

SEQ ID NO: 12 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence features Characteristic symbols: disulfide-bonds Location: 1,15 Location: 3, 11 Sequence Cys Ala Cys Ser Ser Leu Met Asp Lys Glu Cys Val Tyr Phe Cys His 1 5 10 15 Leu Thr Leu Ile Trp 20.

SEQ ID NO: 13 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence characteristics Features symbol: disulfide-bonds Location: 1,15 Location: 3, 11 Sequence Cys Ser Cys Ala Ser Leu Met Asp Lys Glu Cys Val Tyr Phe Cys His 1 5 10 15 Leu Thr Leu Ile Trp 20.

SEQ ID NO: 14 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence features Characteristic symbols: disulfide-bonds Location: 1,15 Location: 3, 11 Sequence Cys Ser Cys Ser Ala Leu Met Asp Lys Glu Cys Val Tyr Phe Cys His 1 5 10 15 Leu Thr Leu Ile Trp 20.

SEQ ID NO: 15 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence characteristics Features symbol: disulfide-bonds Location: 1,15 Location: 3, 11 Sequence Cys Ser Cys Ser Ser Ala Met Asp Lys Glu Cys Val Tyr Phe Cys His 1 5 10 15 Leu Thr Leu Ile Trp 20.

SEQ ID NO: 16 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence characteristics Features symbol: disulfide-bonds Location: 1,15 Location: 3, 11 Sequence Cys Ser Cys Ser Ser Leu Ala Asp Lys Glu Cys Val Tyr Phe Cys His 1 5 10 15 Leu Thr Leu Ile Trp 20.

SEQ ID NO: 17 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence features Characteristic symbols: disulfide-bonds Location: 1,15 Location: 3, 11 Sequence Cys Ser Cys Ser Ser Leu Nle Asp Lys Glu Cys Val Tyr Phe Cys His 1 5 10 15 Leu Thr Leu Ile Trp 20.

SEQ ID NO: 18 Sequence length: 21 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence characteristics Features symbol: disulfide-bonds Location: 1,15 Location: 3, 11 Sequence Cys Ser Cys Ser Ser Trp Leu Asp Lys Glu Cys Val Tyr Phe Cys His 1 5 10 15 Leu Thr Leu Ile Trp 20.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display location C07K 7/64 ZNA 8318-4H // C07K 99:00 A61K 37/02 ABJ

Claims (6)

[Claims] 1. A preventive and / or therapeutic agent for functional decline of organs which occurs during surgery or transplantation of organs, which comprises a compound having an endothelin receptor antagonistic action. 2. The preventive and / or therapeutic agent according to claim 1, wherein the organ is the liver. 3. A compound having an endothelin receptor antagonistic activity is represented by the formula [A]: [Wherein X and Y are each an α-amino acid residue, A
Is a D-acidic-α-amino acid residue, B is a neutral-α-amino acid residue, C is an L-α-amino acid residue, and D is an D-α-amino acid residue having an aromatic ring group. The preventive and / or therapeutic agent according to claim 1, which is a cyclic peptide represented by the formula] or a salt thereof. 4. A cyclic peptide or salt thereof wherein A is a C _3-5 -D-acidic-α-amino acid residue, preferably C
_A compound which is a _3-5 -D-α-aminodicarboxylic acid residue, a C _3-11 -L-α-amino acid residue in which X may be substituted, preferably a heterocyclic group which may have a substituent A compound which is a C _3-5 -L-α-aminodicarboxylic acid residue which may be substituted with a ring group, Y is an L-acidic α-amino acid residue, preferably C _3-5 -L-α-
A compound which is an aminodicarboxylic acid residue, B may be substituted with a C _2-6 -D-neutral-α-amino acid residue which may have a heterocyclic group, preferably a sulfur-containing heterocyclic group A compound which is a good C _2-6 -D-α-aminomonocarboxylic acid residue, C is an L-neutral-α-amino acid residue, preferably C _5-6 -L-α
-A compound that is an aminomonocarboxylic acid residue, or a D-neutral-α-amino acid residue having an aromatic heterocyclic group in which D is optionally acylated, preferably a nitrogen-containing aromatic heterocyclic group The preventive and / or therapeutic agent according to claim 3, which is a compound having a D-neutral-α-amino acid residue. 5. A cyclic peptide or a salt thereof is Cyclo [-D-As
p-Asn (CH ₂ CH ₂ -Ind) -Asp-D-Leu-Leu-D-Trp-], Cyclo 〔-
D-Asp-Trp-Asp-D-Leu-Leu-D-Trp (For)-], Cyclo 〔-DA
sp-Trp-Asp-D-Thg (3) -Leu-D-Trp-], Cyclo 〔-D-Asp-Tr
p-Asp-D-γMeLeu-Leu-D-Trp-], Cyclo 〔-D-Asp-Trp-As
pD-Thg (2) -Leu-D-Trp-], Cyclo 〔-D-Asp-Gln (CH ₂ Ph)-
Asp-D-Leu-Leu-D-Trp-], Cyclo 〔-D-Asp-Asp (R1) -Asp-
D-Leu-Leu-D-Trp-], Cyclo 〔-D-Asp-Asp (R2) -Asp-D-Le
u-Leu-D-Trp-], Cyclo 〔-D-Asp-Orn (COCH ₂ Ph) -Asp-DL
eu-Leu-D-Trp-], Cyclo 〔-D-Asp-Orn (COCH ₂ -Ind) -Asp-
D-Leu-Leu-D-Trp-], Cyclo 〔-D-Asp-Hyp (Bzl) -Asp-DT
hg (2) -Leu-D-Trp-], Cyclo 〔-D-Asp-Gln (Bzl) -Asp-DT
hg (2) -Leu-D-Trp-], Cyclo 〔-D-Asp-Asn (CH ₂ CH ₂ -Ind)-
Asp-D-Thg (2) -Leu-D-Trp-], Cyclo 〔-D-Asp-Asp (R1) -A
sp-D-Thg (2) -Leu-D-Trp-], Cyclo 〔-D-Asp-Asp (R7) -As
pD-Thg (2) -Leu-D-Trp-], Cyclo 〔-D-Asp-Asp (R10) -As
pD-Thg (2) -Leu-D-Trp-], Cyclo 〔-D-Asp-Asp (R12) -As
pD-Thg (2) -Leu-D-Trp-], Cyclo 〔-D-Asp-Asp (R13) -As
pD-Thg (2) -Leu-D-Trp-], Cyclo 〔-D-Cta-Asp (R1) -Asp
-D-Thg (2) -Leu-D-Trp-], Cyclo 〔-D-Cta-Asp (R7) -Asp-
D-Thg (2) -Leu-D-Trp-], Cyclo 〔-D-Cta-Asp (R10) -Asp-
D-Thg (2) -Leu-D-Trp-], Cyclo 〔-D-Cta-Asp (R12) -Asp-
D-Thg (2) -Leu-D-Trp-], Cyclo 〔-D-Cta-Asp (R13) -Asp-
D-Thg (2) -Leu-D-Trp-], Cyclo 〔-D-Asp-Asp (R1) -Asp-D
-Cpg-Leu-D-Trp-], or Cyclo 〔-D-Cta-Asp (R1) -Asp
-D-Cpg-Leu-D-Trp-], The prophylactic and / or therapeutic agent according to claim 3. 6. Cyclo (-D-Asp-Asp (R1) -Asp-D-Thg (2)-
Leu-D-Trp-) disodium salt.